Topical compositions and methods for treating pain

ABSTRACT

Topical compositions and methods for treating pain. The invention provides oil-in-water emulsions comprising an antidepressant; an NMDA-receptor antagonists; a lipophilic component; water; and a surfactant. The compositions induce a local-anesthetic effect when topically administered to intact skin thereby treating or preventing pain, for example, neuropathic pain.

I. FIELD OF THE INVENTION

[0001] The present invention relates to methods for treating orpreventing pain via topical formulations that induce a local-anestheticeffect when applied to intact skin. The compositions comprise anantidepressant and a N-methyl-D-aspartate-receptor antagonist.

II. BACKGROUND OF THE INVENTION

[0002] Pain results from the noxious stimulation of nerve endings.Nociceptive pain is caused by noxious stimulation of nociceptors (e.g.,a needle stick or skin pinch), which then transmit impulses over intactneural pathways to the spinal neurons and then to the brain. Neuropathicpain is caused by damage to neural structures, such as damage toperipheral nerve endings or nociceptors, which become extremelysensitive to stimulation and can generate impulses in the absence ofstimulation (e.g., herpes zoster pain after the rash has healed).Peripheral nerve damage can lead to pathological states where there is areduction in pain threshold (i.e., allodynia), an increased response tonoxious stimuli (hyperalgesia), or an increased response duration(persistent pain). Goodman & Gilman's the Pharmacological Basis ofTherapeutics 529 (Joel G. Hardman et al. eds., 9th ed. 1996); Harrison'sPrinciples of Internal Medicine 53-58 (Anthony S. Fauci et al. eds.,14th ed. 1998).

[0003] In contrast to pain treatment with systemic agents, pain can betreated locally by topically administering a local anesthetic directlyto the painful area to block the nociceptive mechanistic pathway. Localanesthetics prevent the generation and conduction of nociceptive nerveimpulses. Thus, for example, a local anesthetic can be injectedintradermally (non-systemic injection within the skin) or topicallyapplied at the pain area. Advantages of topical local-anestheticadministration over systemic administration of pain relievers includedecrease or preclusion of side effects, improved patient compliance, andreversible action (i.e., the action can be reversed by removing theanesthetic from the application site). Transdermal and Topical DrugDelevery Systems 33-112 (Tapash K. Ghosh et al. eds., 1997).

[0004] A variety of drug classes have local-anesthetic properties andcan be administered in topical formulations. Traditional localanesthetics or sodium-channel blockers, such as lidocaine prevent thegeneration and conduction of nerve impulses by decreasing or preventingthe large transient increase in the permeability of excitable membranesto Na+. Other agents with local-anesthetic properties includeanalgesics, such as non-steroidal anti-inflammatories (“NSAIDs”), see,for example, Transdermal and Topical Drug Delivery Systems 87-93 (TapashK. Ghosh et al. eds., 1997) and opioids, such as morphine. See e.g.,U.S. Pat. No. 5,948,389 (issued Sep. 7, 1999); Christoph Stein &Alexander Yassouridis 71 Pain 119 (1997).

[0005] N-methyl-D-aspartate (“NMDA”) receptor antagonists, such asketamine have local-aesthetic properties and topical administration isas an effective neuropathic pain treatment. See, for example, U.S. Pat.No. 5,817,699 (issued Oct. 6, 1998). In another example, topicaladministration of antidepressant medications, such as amitriptyline, hasbeen reported effective for neuropathic pain treatment. See, forexample, U.S. Pat. No. 6,211,171 (issued Apr. 3, 2001); J. Sawynok etal., 82 PAIN 149 (1999). In addition, topical administration of acombination of a tricyclic antidepressant and an NMDA-receptorantagonist is reported to have excellent local-anesthetic propertieswhen topically applied and is useful for treatment of neuropathic pain,U.S. Pat. No. 6,197,830 (issued Mar. 6, 2001).

[0006] But even though topical local-anesthetic administration to intactskin is routinely used to treat minor indications, it has not foundsignificant use for treating more severe nociceptive and neuropathicpain because it is difficult to get significant concentrations throughthe skin barrier. Because of the skin's drug-permeation resistance, aslittle as about 1 percent and usually no more than about 15 percent of adrug in a topical formulation is bioavailable (Transdermal and TopicalDrug Delivery Systems 7 (Tapash K. Ghosh et al. eds., 1997)). Anotherproblem with topical administration of pain relievers is stability ofthe composition. Local-anesthetics emulsion compositions are inherentlyunstable, and phase separation can occur during shipment and storage.Furthermore, many topical local-anesthetic compositions suffer fromoxidative instability. Lecithin compositions are routinely used as basesfor topical local-aesthetic compositions, but are highly oxidativelyunstable (Am. Pharm. Assoc., Handbook of Pharmaceutical Excipients292-294, 292 (Arthur H. Kibbe ed., 3rd ed. 2000)). For example, U.S.Pat. No. 6,197,830 (issued Mar. 6, 2001) describes a lecithin-basedcomposition for topically administering a combination of anNMDA-receptor antagonist and a tricyclic antidepressant and U.S. Pat.Nos. 5,817,699 (issued Oct. 6, 1998) and 6,017,961 (issued Jan. 25,2000) describe topical administration of ketamine in pluronic lecithinorganogel.

[0007] In sum, topical local-anesthetic administration has advantagesover systemic administration of pain relievers. Unfortunately, topicallocal-anesthetic compositions suffer from instability and poorskin-penetration properties, which limit their use to less severe pain.What are needed are stable topical local-anesthetic compositions withgood skin-penetration properties. Particularly, stable, skin-penetratingcompositions comprising a combination of an antidepressant and anNMDA-receptor antagonists are needed.

[0008] Citation or identification of any reference in the Backgroundsection of this application is not an admission that such reference isprior art to the present invention.

III. SUMMARY OF THE INVENTION

[0009] The invention provides methods and topical compositions fortreating or preventing pain. The compositions of the invention can betopically administered to intact skin to provide a local-anestheticeffect thereby treating or preventing pain, for example, neuropathicpain. In one embodiment, the invention provides stable, skin penetratingcompositions for topical administration comprising a combination of anantidepressant and an NMDA-receptor antagonist.

[0010] In a second embodiment, the invention provides an emulsioncomprising:

[0011] (a) an antidepressant or a pharmaceutically acceptable saltthereof;

[0012] (b) an NMDA-receptor antagonists or a pharmaceutically acceptablesalt thereof;

[0013] (c) a lipophilic component;

[0014] (d) water; and

[0015] (e) a surfactant, wherein the emulsion is an oil-in-wateremulsion. Preferably, the mean oil-droplet size is within the range ofabout 0.01 microns to about 100 microns, more preferably, within therange of about 0.1 microns to about 10 microns.

[0016] In another embodiment, the invention relates to a patchcomprising:

[0017] (a) an antidepressant or a pharmaceutically acceptable saltthereof;

[0018] (b) an NMDA receptor antagonists or a pharmaceutically acceptablesalt thereof;

[0019] (c) a lipophilic component;

[0020] (d) water; and

[0021] (e) a surfactant, wherein the emulsion is an oil in wateremulsion.

[0022] In still another embodiment, the invention provides a method oftreating or preventing pain in a mammal comprising topicallyadministering to the skin of a mammal in need thereof an emulsioncomprising:

[0023] (a) a therapeutically effective amount of an antidepressant or apharmaceutically acceptable salt thereof;

[0024] (b) a therapeutically effective amount of an NMDA-receptorantagonists or a pharmaceutically acceptable salt thereof;

[0025] (c) a lipophilic component;

[0026] (d) water; and

[0027] (e) a surfactant, wherein the emulsion is an oil-in-wateremulsion.

[0028] In still another embodiment, the invention relates to a method ofinducing local anesthesia in a mammal comprising topically administeringto the skin of a mammal in need thereof an emulsion comprising:

[0029] (a) a therapeutically effective amount of an antidepressant or apharmaceutically acceptable salt thereof;

[0030] (b) a therapeutically effective amount of an NMDA-receptorantagonists or a pharmaceutically acceptable salt thereof;

[0031] (c) a lipophilic component;

[0032] (d) water; and

[0033] (e) a surfactant, wherein the emulsion is an oil-in-wateremulsion.

[0034] The present invention may be understood more fully by referenceto the following figures, detailed description and illustrativeexamples, which are intended to exemplify non-limiting embodiments ofthe invention.

IV. DEFINITIONS

[0035] As used herein, the phrase “composition of the invention” refersto an oil-in-water emulsion having a mean droplet size within the rangeof 0.01 microns to 100 microns comprising:

[0036] (1) a therapeutically effective amount of an antidepressant, apharmaceutically acceptable salts thereof, a complex thereof (e.g.,hydrates, solvates, and clathrates), a prodrug thereof, or anystereoisomeric forms or mixtures of stereoisomeric forms thereof (e.g.,geometrical isomers, enantiomers,. diastereomers, racemates, or mixturesthereof);

[0037] (2) a therapeutically effective amount of an NMDA-receptorantagonists, a pharmaceutically acceptable salts thereof, a complexthereof (e.g., hydrates, solvates, and clathrates), a prodrug thereof,or any stereoisomeric forms or mixtures of stereoisomeric forms thereof(e.g., geometrical isomers, enantiomers, diastereomers, racemates, ormixtures thereof);

[0038] (3) a lipophilic component;

[0039] (4) water; and

[0040] (5) a surfactant.

[0041] As used herein, a “therapeutically effective amount” of anantidepressant or an NMDA-receptor antagonist means the amount of theantidepressant or the NMDA-receptor antagonist required in a compositionof the invention to induce a local-anesthetic effect sufficient to treator ameliorate pain in a mammal.

[0042] As used herein, the term mammal means any mammal, for example,but not limited to humans; pets, such as dogs and cats; farm mammals,such as horses, cows, pigs, and sheep; and laboratory animals, such asmonkeys, guinea pigs, rats, and mice. Preferably, a “mammal” is a human.

[0043] As used herein, the term “intradermal administration” meansadministration of a pharmaceutical to the skin of a mammal, preferably ahuman, to deliver the pharmaceutical to the local tissue under andaround the site of administration. Preferably, intradermaladministration is effected without absorption of the pharmaceutical intothe mammal's blood stream. The purpose of intradermal administration isto elicit a local affect in contrast to transdermal administration wherethe objective is to transfer the pharmaceutical through the skin andinto the blood stream for a systemic effect.

[0044] As used herein, the term “topical administration” or “topicaldelivery” means intradermal administration of a pharmaceutical byadministration of the pharmaceutical or a composition comprising thepharmaceutical to intact skin. For example, by rubbing a composition ofthe invention onto an area of intact skin or by placing an intradermalpatch comprising a composition of the invention onto an area of intactskin.

[0045] The term “topical composition” means a pharmaceutical compositiondesigned for topical administration and containing a pharmaceutical.

[0046] As used herein, the phrase “intradermally-acceptable” means anypharmaceutical, excipient or other component of a topical formulationthat is safe or approved for intradermal or topical administration inmammals.

[0047] The phrase “pharmaceutically acceptable salt(s),” as used hereinincludes, but is not limited to, salts of acidic or basic groups thatmay be present in the compounds of the invention. Compounds of theinvention that are basic in nature are capable of forming a wide varietyof salts with various inorganic and organic acids. The acids that may beused to prepare pharmaceutically acceptable salts of such basiccompounds are those that form salts comprising pharmacologicallyacceptable anions including, but not limited to, acetate,benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calciumedetate, camsylate, carbonate, chloride, bromide, iodide, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydroxynaphthoate, isethionate, lactate, lactobionate,malate, maleate, mandelate, mesylate, methylsulfate, muscate, napsylate,nitrate, panthothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, succinate, sulfate, tannate, tartrate, teoclate,triethiodide, and pamoate (i.e.,1,1′-methylene-bis-(2-hydroxy-3naphthoate)). Compounds of the inventionthat include an amino moiety also can form pharmaceutically acceptablesalts with various amino acids, in addition to the acids mentionedabove. Compounds of the invention that are acidic in nature are capableof forming base salts with various pharmacologically acceptable cations.Examples of such salts include alkali metal or alkaline earth metalsalts and, particularly, calcium, magnesium, sodium, lithium, zinc,potassium, and iron salts.

[0048] As used herein, the term “solvate” means a compound of theinvention or a salt thereof, that further includes a stoichiometric ornon-stoichiometric amount of a solvent bound by non-covalentintermolecular forces. Preferred solvents are volatile, non-toxic,and/or acceptable for topical administration to humans.

[0049] As used herein, the term “hydrate” means a compound of theinvention or a salt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces. The term “clathrate” means a compound of the invention or a saltthereof in the form of a crystal lattice that contains spaces (e.g.,channels) that have a guest molecule (e.g., a solvent or water) trappedwithin.

[0050] The term “prodrug” refers to a compound that, followingadministration in a mammal, converts, via a biotransformation, into anantidepressant or an NMDA-receptor antagonist in vivo. Prodrugs can besynthesized using well-known methods, such as those described by 1Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982(Manfred E. Wolff ed., 5th ed. 1995).

[0051] As used herein, an “emulsion” means a dispersed system containingat lease two immiscible phases (a lipophilic phase and a hydrophilic oraqueous phase), wherein one immiscible phase is dispersed within theother in the form of droplets. Emulsions are thermodynamically unstableas a result of excess free energy associated with the surface of thedroplet. A stable emulsion must contain at least three components, i.e.,a dispersion medium, a dispersed phase, and an emulsifying agent. Asused herein, a “oil-in-water type emulsion” is a stable emulsion inwhich the aqueous phase is the dispersion medium and the lipophiliccomponent is the dispersed phase. Several tests are available todetermine whether an emulsion is an oil-in-water type emulsion or awater-in-oil type emulsion: for example, the dilution test, theconductivity test, and the dye solubility test, which tests aredescribed in 1 Remington: the Science and Practice of Pharmacy 282-291(Alfonso R. Gennaro ed., 19th ed. 1995), hereby expressly incorporatedherein by reference.

V. DETAILED DESCRIPTION OF THE INVENTION

[0052] The compositions of the invention comprise an antidepressant andan NMDA-receptor antagonist in a colloidal dispersion (emulsion). Thecolloidal dispersion comprises an aqueous phase, a lipophilic phase, anda surfactant system, wherein the lipophilic phase is dispersed withinthe aqueous phase (oil-in-water emulsion) and the mean-droplet size iswithin the range of about 0.01 microns to about 100 microns, preferablyabout 0.1 microns to 10 about microns. In a preferred embodiment, thecompositions of the invention further comprise a stiffening agent and ahydrophobic surfactant. When topically administered to a mammal, thecompositions of the invention can deliver a combination of anantidepressant and an NMDA-receptor antagonist through intact skin at ahigh flux rate to induce local anesthesia and thereby treat, ameliorate,or prevent neuropathic pain. Furthermore, the compositions of theinvention are stable both physically (resists coalescing of droplets andOstwald ripening) and chemically stable (e.g., resist oxidation) andimpart a soothing feeling when administered.

[0053] A. Pain Indications

[0054] The compositions and methods of the invention can be used totreat or prevent any indication resulting from noxious stimulation ofperipheral nociceptors. The compositions and methods of the inventionare effective to induce local anesthesia and to treat neuropathic pain.As used herein the term “neuropathic pain” refers to neuropathic-painsyndromes, that is, pain due to lesions or dysfunction in the nervoussystem. The compositions and methods of the invention can be used totreat or prevent pain related to or induced by the following diseases,trauma, or conditions: general neuropathic conditions, such asperipheral neuropathy, phantom pain, reflex-sympathetic dystrophy,causalgia, syringomyelia, and painful scar; specific neuralgias at anylocation of the body; back pain; diabetic neuropathy; alcoholicneuropathy; metabolic neuropathy; inflammatory neuropathy;chemotherapy-induced neuropathy, herpetic neuralgias; traumaticodontalgia; endodontic odontalgia; thoracic-outlet syndrome; cervical,thoracic, or lumbar radiculopathies with nerve compression; cancer withnerve invasion; traumatic-avulsion injuries; mastectomy, thoracotomypain; spinal-cord-injury; stroke; abdominal-cutaneous nerve entrapments;tumors of neural tissues; arachnoiditis; stump pain; fibromyalgia;regional sprains or strains; myofascial pain; psoriatic arthropathy;polyarteritis nodosa; osteomyelitis; burns involving nerve damage;AIDS-related pain syndromes; connective tissue disorders, such assystemic lupus erythematosis, systemic sclerosis, polymyositis, anddermatomyositis; and inflammatory conditions, such as acute inflammation(e.g. trauma, surgery and infection) or chronic inflammation (e.g.,arthritis and gout).

[0055] B. Antidepressants

[0056] The term “antidepressant” means any compound or composition knownor to be discovered that, when tested according to standard in vivo orin vitro assays, displays receptor-binding properties or othermechanistic properties associated with the clinically approvedantidepressants or any compound or composition known or to be discoveredthat has demonstrated clinical efficacy in treating depression inmammals including those compounds and compositions that have beenapproved for treating depression in humans.

[0057] Classes of antidepressant agents include norepineplrine-reuptakeinhibitors (NRIs”), selective-serotonin-reuptake inhibitors (SSRIs),monoamine-oxidase inhibitors (MAOIs),serotonin-and-noradrenaline-reuptake inhibitors (“SNRIs);corticotropin-releasing factor (CRF) antagonists, α-adrenoreceptorantagonists; NK1-receptor antagonists, 5-HT_(1A)-receptor agonist,antagonists, and partial agonists, atypical antidepressants, and otherantidepressants.

[0058] An antidepressant can contain one or more chiral centers and/ordouble bonds and, therefore, exist as stereoisomers, such as double-bondisomers (i.e., geometric isomers), enantiomers, or diastereomers. Asused herein, the term “antidepressant” encompass all such enantiomersand stereoisomers, that is, both the stereomerically-pure form (e.g.,geometrically pure, enantiomerically pure, or diastereomerically pure)and enantiomeric and stereoisomeric mixtures, e.g., racemates. The term“antidepressant” further encompasses all pharmaceutically acceptablesalts, all complexes (e.g., hydrates, solvates, and clathrates), and allprodrugs of antidepressants.

[0059] Notably, the methods of the invention involve topicaladministration, thus “antidepressants” unsuitable for systemicadministration in mammals, because of toxicity or otherwise, may stillbe suitable for topical administration in combination with anNMDA-receptor antagonist according to the compositions and methods ofthe invention. Antidepressants suitable for use in the invention can beidentified by testing antidepressant compounds for local-anesthetic andperipheral antinociceptive properties according to standard pain models.See, for example, J. Sawynok et al., 82 Pain 149 (1999); J. Sawynok etal., 80 Pain 45 (1999), both of which citations are hereby expresslyincorporated by reference herein.

[0060] Preferably an antidepressant is a norepinephrine-reuptakeinhibitor, more preferably, a tricyclic antidepressant, most preferably,amitriptyline, even more preferably amitriptyline hydrochloride.

[0061] 1. Norepinephrine-reuptake Inhibitors

[0062] The term “antidepressant” as used herein includes compounds thatwhen administered systemically in a mammal, inhibitnorepinephrine-reuptake (“norepinephrine-reuptake inhibitors”) or thatwhen tested according to standard in vivo or in vitro assays, displayreceptor-binding properties or other mechanistic properties associatedwith norepinephrine-reuptake inhibitors. One of skill in the art canreadily identify norepinephrine-reuptake inhibitors by in vivo and invitro assays. For example, norepinephrine-reuptake inhibitors can beidentified by adapting the in vitro test method described by Wong etal., 61 J. Pharm. Exp. Therap. 222 (1982); P. Skolnick et al., 86 BR. J.Pharmacology 637-644 (1985), hereby expressly incorporated herein byreference. Examples of norepinephrine-reuptake inhibitors include, butare not limited to amitriptyline, desmethylamitriptyline, clomipramine,doxepin, imipramine, imipramine -oxide, trimipramine; adinazolam,amiltriptylinoxide, amoxapine, desipramine, maprotiline, nortriptyline,protriptyline, amineptine, butriptyline, demexiptiline, dibenzepin,dimetacrine, dothiepin, fluacizine, iprindole, lofepramine, melitracen,metapramine, norclolipramine, noxiptilin, opipramol, perlapine,pizotyline, propizepine, quinupramine, reboxetine, tianeptine, andpharmaceutically acceptable salts thereof. Examples of othernorepinephrine-reuptake inhibitors include the tricyclic compoundsencompassed by the generic formula disclosed in U.S. Pat. No. 6,211,171(issued Apr. 30, 2001) column 9, lines 30-65 and pharmaceuticallyacceptable salts thereof, hereby expressly incorporated herein byreference.

[0063] 2. Serotonin-Reuptake Inhibitors

[0064] The term “antidepressants” also includes compounds that inhibitreuptake of serotonin (“serotonin reuptake inhibitors”) whensystemically administered in mammals or that when tested according tostandard in vivo or in vitro assays, display receptor-binding propertiesor other mechanistic properties associated with serotonin-reuptakeinhibitors. One of skill in the art can readily identifyserotonin-reuptake inhibitors. For example, serotonin-reuptakeinhibitors can be identified by adapting the in vitro test methodsdescribed in Wong, et al., 8 Neuropsychopharmacology 337 (1993); U.S.Pat. No., 6,225,324 (issued May 1, 2001), column 20, lines 20-67; andU.S. Pat. No. 5,648,396 (issued Jul. 15, 1997) column 15, line 33through column 16, line 44, hereby expressly incorporated herein byreference. Examples of serotonin-reuptake inhibitors include, but arenot limited to, binedaline, m-chloropiperzine, citalopram, duloxetine,etoperidone, femoxetine, fluoxetine, fluvoxamine, indalpine,indeloxazine, milnacipran, nefazodone, oxaflazone, paroxetine,prolintane, ritanserin, sertraline, tandospirone, venlafaxine andzimeldine, and pharmaceutically acceptable salts thereof.

[0065] 3. Monoamine-oxidase inhibitors

[0066] The term “antidepressant” as used herein includes compounds thatwhen administered systemically in a mammal, act as monoamine-oxidaseinhibitors (“MAOIs”) or that when tested according to standard in vivoor in vitro assays, inhibit monoamine oxidase. One of skill in the artcan readily identify MAOIs by in vivo and in vitro assays. For example,MAOIs can be identified by adapting the monoamine-oxidase inhibitoryassay described in 12 Biochem. Pharmacol. 1439 (1963) and Kinemuchi etal., 35 J. Neurochem. 109 (1980); U.S. Pat. No. 6,096,771 (issued Aug.1, 2000), all of which citations are hereby expressly incorporatedherein by reference.

[0067] Examples of non-selective MAO inhibitors include, but are notlimited to, amiflamine, vanoxerine (boxeprazine), AGN 2253 (NicholasKiwi), iproniazid, isocarboxazid, M-3-PPC (Draxis), nialamid,phenelzine, pargyline, and tranylcypromine and pharmaceuticallyacceptable salts thereof.

[0068] Examples selective MAO A inhibitors include, but are not limitedto, clorgyline, cimoxatone, befloxatone, brofaromine, bazinaprine,BW-616U (Burroughs Wellcome), BW-1370U87 (Burroughs Wellcome), CS-722(RS-722) (Sankyo), E-2011 (Eisai), harmine, harmaline, moclobemide,PharmaProjects 3975 (Hoechst), RO 41-1049 (Roche), RS-8359 (Sankyo),T-794 (Tanabe Seiyaku), toloxatone, K-Y 1349 (Kalir and Youdim),LY-51641 (Lilly), LY-121768 (Lilly), M&B 9303 (May & Baker), MDL 72394(Marion Merrell), MDL 72392 (Marion Merrell), sercloremine, and MO 1671and pharmaceutically acceptable salts thereof.

[0069] Other MAO A inhibitors include budipine, caroxazone, D- 1711(Biocodex), fezolamine, FLA-334 (RAN-1 13) (Astra), FLA-289 (FLA-299,FLA-365, FLA-384, FLA-463, FLA-727) (Astra), K-1 1566 (Pharmacia Upjohn,Farmitalia), K-1 1829 (Pharmacia Upjohn, Farmitalia), metralindole,MPCPAM (Yissum), PharmaProjects 227 (Syntex/Roche), PharmaProjects 2806(Fournier), PharmaProjects 1122, PharmaProjects 3311 (Roche),PharmaProjects 4433 (Roche), RS-2232 (Sankyo), and UP-614-04(Bristol-Myers) and pharmaceutically acceptable salts thereof.

[0070] Other MAO inhibitors include bifemelane, brofaromide, hypericin,iproclozide, medifoxamine, nialamide, octamoxin, phenoxypropaazine,pivalyl benzhydrazine, prodipine, selegiline, and benmoxine andpharmaceutically acceptable salts thereof.

[0071] 4. Serotonin- and Noradrenalin-Reuptake Inhibitors

[0072] The term “antidepressant” as used herein includes compounds thatwhen administered systemically in a mammal, act as serotonin- andnoradrenaline-reuptake inhibitors (“SNRIs”) or that when testedaccording to standard in vivo or in vitro assays, displayreceptor-binding properties or other mechanistic properties associatedwith serotonin- and noradrenalin-reuptake inhibitors. One of skill inthe art can readily identify SNRIs by in vivo and in vitro assays. Forexample, SNRIs can be identified by adapting the in vitro test methoddescribed in U.S. Pat. No. 6,172,097 (issued Jan. 9, 2001), herebyexpressly incorporated herein by reference. Examples of SNRIs include,but are not limited to, mirtazapine, and venlafaxine andpharmaceutically acceptable salts thereof.

[0073] 5. Corticotropin-Releasing-Factor Antagonists

[0074] The term “antidepressant” as used herein includes compounds thatwhen administered systemically in a mammal, act ascorticotropin-releasing factor antagonists (“CRF antagonists”) or thatwhen tested according to standard in vivo or in vitro assays, displayreceptor-binding properties or other mechanistic properties associatedwith CRF antagonists. One of skill in the art can readily identify CRFantagonists by in vivo and in vitro assays. For example, CRF antagonistscan be identified by adapting the in vitro test method described in U.S.Pat. No. 6,218,391 (issued Apr. 17, 2001), hereby expressly incorporatedherein by reference.

[0075] Examples of CRF antagonists include, but are not limited to,those described in U.S. Pat. Nos. 6,191,131 (issued Feb. 20, 2001);6,174,192 (issued Jan. 16, 2001); 6,133,282 (issued Oct. 17,2000); PCTPatent Application Publication Nos. WO 94/13643, WO 94/13644, WO94/13661, WO 94/13676 and WO 94/13677, and pharmaceutically acceptablesalts thereof, all of which patents and publications are herebyexpressly incorporated herein by reference.

[0076] 6. α-Adrenoreceptor Antagonists

[0077] The term “antidepressant” as used herein includes compounds thatwhen administered systemically in a mammal, act as α-adrenoreceptorantagonists or that when tested according to standard in vivo or invitro assays, act as α-adrenoreceptor antagonists. One of skill in theart can readily identify α-adrenoreceptor antagonists by in vivo and invitro assays. For example, α-adrenoreceptor antagonists can beidentified by adapting the in vitro test method described in U.S. Pat.No. 6,150,389 (issued Nov. 21, 2000), hereby expressly incorporatedherein by reference.

[0078] Examples of α-adrenoreceptor antagonists include, but are notlimited to, phentolamine and those described in U.S. Pat. No. 6,150,389and pharmaceutically acceptable salts thereof.

[0079] 7. NK1-Receptor Antagonists The term “antidepressant” as usedherein includes compounds that when administered systemically in amammal, act as NK1-receptor antagonists (Neurokinn 1 substance Preceptor antagonists) or that when tested according to standard in vivoor in vitro assays, act as NK1-receptor antagonists. One of skill in theart can readily identify NK1-receptor antagonists by in vivo and invitro assays. For example, NK1-receptor antagonists can be identified byadapting the NK1-receptor-binding assay described in U.S. Pat. No.6,117,855 (issued Sep. 12, 2000), hereby expressly incorporated hereinby reference.

[0080] Examples of NK1-receptor antagonists include, but are not limitedto, those described in PCT Patent Application Publication Nos. WO95/16679, WO 95/18124, WO 95/23798, and European Patent SpecificationNo. 0 577 394 and pharmaceutically acceptable salts thereof, all ofwhich publications and patent are hereby expressly incorporated hereinby reference.

[0081] 8. 5-HT_(1A)-receptor agonist, Antagonists, and Partial Agonists

[0082] The term “antidepressant” as used herein includes compounds thatwhen administered systemically in a mammal, act as 5-HT_(1A-)receptoragonist, antagonists, and partial agonists (“5-HT_(1A) agents”) or thatwhen tested according to standard in vivo or in vitro assays, act as5-HT_(1A-)receptor agonist, antagonists, and partial agonists. One ofskill in the art can readily identify 5-HT_(1A) agents by in vivo and invitro assays. For example, 5-HT_(1A) agents can be identified byadapting the 5-HT_(1A) receptor binding assays described in U.S. Pat.No. 6,255,302 (issued Jul. 3, 2001) or 6,239,194 (issued May 29, 2001),which patents are hereby expressly incorporated herein by reference.Examples of 5-HT_(1A) agents include, but are not limited to, buspirone,flesinoxan, gepirone, and ipsapirone, and pharmaceutically acceptablesalts thereof and those disclosed in U.S. Pat. Nos. 6,255,302; 6,245,781(issued Jun. 12, 2001); and 6,242,448 (issued Jun. 5, 2001). An exampleof a compound with 5-HT_(1A) receptor antagonist/partial agonistactivity is pindolol.

[0083] 9. Atypical Antidepressants

[0084] The term “antidepressants” also includes atypicalantidepressants. Examples of atypical antidepressants include, but arenot limited to bupropion, dimethazan, fencamine, fenpentadiol,levophacetoperance, metralindone, mianserin, cotinine, rolicyprine,rolipram, nefopam, lithium, trazodone, viloxazine, and sibutramine andpharmaceutically acceptable salts thereof.

[0085] 10. Other Antidepressants

[0086] The term “antidepressants” also includes a wide variety of otherdrugs that are thought to have antidepressant activity including, butnot limited to, nomifensine, oxitriptan, oxypertine, thiazesim,adrafinil, benactyzine, butacetin, dioxadrol, febarbamate,hematoporphyrin, minaprine, piberaline, pyrisuccideanol, roxindole,rubidium chloride, sulpride, thozalinone, tofenacin, 1-tryptophan,alaproclate, amitriptyline-chlordiazepoxide combination, atipamezole,azamianserin, bazinaprine, befuraline, binodaline, bipenamol,cericlamine, cianopramine, cimoxatone, clemeprol, clovoxamine,dazepinil, deanol, enefexine, estazolam, fezolamine, fluotracen,idazoxan, levoprotiline, litoxetine, montirelin, nebracetam,norfluoxetine, orotirelin, oxaflozane, pinazepam, pirlindone,setiptiline, sulbutiamine, sulpiride, teniloxazine, thymoliberin,tiflucarbine, tofisopam, tomoxetine, veralipride, viqualine, zimelidineand zometapine, and pharmaceutically acceptable salts thereof, and St.John's wort herb or hypericum perforatum, or extracts thereof.

[0087] 11. Concentration of Antidepressant in Compositions of theInvention The amount of antidepressant in compositions of the inventionwill vary according to the type and identity of the antidepressant, theconcentration and identity of the NMDA-receptor antagonist, and thepainful indiction treated. Dosages and concentrations for a particularantidepressants can be optimized according to routine experiments usingwell-known pain models, for example, those described in J. Sawynok etal., 82 Pain 149 (1999) and J. Sawynok et al., 80 Pain 45 (1999).

[0088] In general, the amount of antidepressant in the composition is ofthe invention is within the range of from about 0.1 percent to about 10percent of the total weight of the composition, more preferably, of fromabout 0.5 percent to about 8 percent, still more preferably, of fromabout 1 percent to about 5 percent of the total weight of thecomposition.

[0089] C. N-Methyl-D-Aspartate Receptor Antagonists

[0090] The NMDA receptor is a cell-surface protein complex, widelydistributed in the mammalian central nervous system that belongs to theclass of ionotropic-glutamate receptors. It is involved inexcitatory-synaptic transmission and the regulation of neuronal growth.The structure comprises a ligand-gated/voltage-sensitive ion channel.The NMDA receptor is highly complex and is believed to contain at leastfive distinct binding (activation) sites: a glycine-binding site, aglutamate-binding site (NMDA-binding site); a PCP-binding site, apolyamine-binding site, and a zinc-binding site. In general, a receptorantagonist is a molecule that blocks or reduces the ability of anagonist to activate the receptor. As used herein, an “NMDA-receptorantagonist” means any compound or composition, known or to bediscovered, that when contacted with an NMDA receptor in vivo or invitro, inhibits the flow of ions through the NMDA-receptor ion channel.

[0091] An NMDA-receptor antagonist can contain one or more chiralcenters and/or double bonds and, therefore, exist as stereoisomers, suchas double-bond isomers (i.e., geometric isomers), enantiomers, ordiastereomers. As used herein, the term “NMDA-receptor antagonist”encompass all such enantiomers and stereoisomers, that is, both thestereomerically-pure form (e.g., geometrically pure, enantiomericallypure, or diastereomerically pure) and enantiomeric and stereoisomericmixtures, e.g., racemates. The term “NMDA-receptor antagonist” furtherencompasses all pharmaceutically acceptable salts, all complexes (e.g.,hydrates, solvates, and clathrates), and all prodrugs of NMDA-receptorantagonist.

[0092] NMDA-receptor antagonist suitable for use in the invention can beidentified by testing NMDA-receptor antagonist for local-anesthetic andperipheral antinociceptive properties according to standard pain models.See e.g., J. Sawynok et al., 82 Pain 149 (1999); J. Sawynok et al., 80Pain 45 (1999).

[0093] Preferably, the NMDA-receptor antagonist is a non-competitiveNMDA-receptor antagonists, more preferably, ketamine, even morepreferably, ketamine hydrochloride.

[0094] 1. N-methyl-D-aspartate Receptor Antagonists That Block The NMDAReceptor at the Glycine Binding Site

[0095] As used herein the meaning of the phrase “NMDA-receptorantagonist”encompasses any compound or composition that antagonizes theNMDA receptor by binding at the glycine site. For a review onglycine-site NMDA-receptor antagonists, see Leeson, P. D., Glycine SiteN-Methyl-D-Aspartate Receptor Antagonists, Chapter 13 in Drug Design forNeuroscience, (Kozikowski, A. P. ed. 338-381, 1993). Glycine-siteNMDA-receptor antagonists can be identified by standard in vitro and invivo assays. See, for example, the assays described in U.S. Pat. No.6,251,903 (issued Jun. 26, 2001); U.S. Pat. No. 6,191,165 (issued Feb.20, 2001; Grimwood et al. 4 Molecular Pharmacology 923 (1992); Yoneda etal 62 J. Neurochem. 102 (1994); and Mayer et al. J. Neurophysiol. 645(1988), all of which citations are hereby expressly incorporated hereinby reference.

[0096] Glycine-site NMDA-receptor antagonists include, but are notlimited to, glycinamide, threonine, D-serine, felbamate,5,7-dichlorokynurenic acid, and 3-amino-1-hydroxy-2-pyrrolidone(HA-966), diethylenetriamine, 1,10-diaminodecane, 1,12-diaminododecane,and ifenprodil and those described in U.S. Pat. Nos. 6,251,903; U.S.Pat. No. 5,914,403 (issued Jun. 22, 199); U.S. Pat. No. 5,863,916(issued Jan. 26, 1999); U.S. Pat. No. 5,783,700 (issued Jul. 21, 1998);and U.S. Pat. No. 5,708,168 (issued Jan. 13, 1998), all of which patentsare hereby expressly incorporated herein by reference.

[0097] 2. N-methyl-D-aspartate Receptor Antagonists That Block The NMDAReceptor at the Glutamate Binding Site

[0098] As used herein the meaning of the phrase “NMDA-receptorantagonist”encompasses any compound or composition that antagonizes theNMDA receptor by binding at the glutamate site also referred to hereinas “competitive NMDA-receptor antagonists”; see, for example, Olney &Farber, 13 Neuropsychopharmacology 335 (1995).

[0099] Competitive NMDA antagonists include, but are not limited to,3-((−)-2carboxypiperazin-4-ylpropyl-1-phosphate (CPP);3-(2-carboxypiperzin-4-yl)-prpenyl-1-phosphonate (CPP-ene);1-(cis-2-carboxypiperidine-4-yl)methyl-1-phosphonic acid (CGS 19755),D-2-Amino-5-phosphonopentanoic acid (AP5); 2-amino-phosphonoheptanoate(AP7); D,L-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acidcarboxyethyl ester (CGP39551); 2-amino-4-methyl-5-phosphono-pent-3-enoicacid (CGP 40116); (4-phosphono-but-2-enylamino)-acetic acid (PD 132477);2-amino-4-oxo-5-phosphono-pentanoic acid (MDL 100,453);3-((phosphonylmethyl)-sulfinyl)-D,L-alanine;amino-(4phosphonomethyl-phenyl)-acetic acid (PD 129635);2-amino-3-(5-chloro-1phosphonomethyl-1H-benzoimidazol-2-yl)-propionicacid; 2-amino-3-(3-phosphonomethyl-quinoxalin-2-yl)-propionic acid;2-amino-3-(5-phosphonomethyl-biphenyl-3-yl)-propionic acid (SDZ EAB515); 2-amino-3-[2-(2-phosphono-ethyl)-cyclohexyl]-propionic acid (NPC17742); 4-(3-phosphono-propyl)-piperazine-2-carboxylic acid (D-CPP);4-(3-phosphono-allyl)-piperazine-2-carboxylic acid (D-CPP-ene);4-phosphonomethyl-piperidine-2carboxylic acid (CGS 19755);3-(2-phosphono-acetyl)-piperidine-2-carboxylic acid (MDL 100,925);5-phosphono-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (SC48981);5-(2-phosphono-ethyl)-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid(PD 145950); 6phosphonomethyl-decahydro-isoquinoline-3-carboxylic acid(LY 274614); 4-(1H-tetrazol-5ylmethyl)-piperidine-2-carboxylic acid (LY233053 and 235723);6-(1H-Tetrazol-5ylmethyl)-decahydro-isoquinoline-3-carboxylic acid (LY233536). References that disclose other competitive NMDA-receptorantagonists as well as assays for identifying competitive NMDA-receptorantagonists include Jia-He Li, et al., 38 J. Med. Chem. 1955 (1995);Steinberg et al, 133 Neurosci. Lett. 225 (1991); Meldrum et al., 11Trends Pharmacol. Sci., 379 (1990); Willetts et al., 11 TrendsPharmacol. Sci. 423 (1990); Faden et al., 13 Trends Pharmacol. Sci. 29(1992); Rogawski 14 Trends Pharmacol. Sci. 325 (1993); Albers et al, 15Clinical Neuropharm. 509 (1992); Wolfe et al., 13 Am. J Emerg. Med., 174(1995); and Bigge, 45 Biochem. Pharmacol. 1547 (1993), all of whichcitations are hereby expressly incorporated herein by reference.

[0100] 3. N-methyl-D-aspartate Receptor Antagonists That Block The NMDAReceptor at the PCP Binding Site

[0101] As used herein the meaning of the phrase “NMDA-receptorantagonist” encompasses any compound or composition that antagonizes theNMDA receptor by binding at the PCP (phencyclidine) site, referred toherein as “non-competitive NMDA-receptor antagonists”; see, for example,Bigge 45 Biochem. Pharmacol. 1547 (1993).

[0102] Non-competitive NMDA-receptor antagonists can be identified usingroutine assays, for example, those described in U.S. Pat. Nos. 6,251,948(issued Jun. 26, 2001); U.S. Pat. No. 5,985,586 (issued Nov. 16, 1999),and U.S. Pat. No. 6,025,369 (issued Feb. 15, 2000); Jacobson et al., 110J. Pharmacol. Exp. Ther. 243 (1987); and Thurkaufet al., 31 J. Med.Chem. 2257 (1988), all of which citations are hereby expresslyincorporated herein by reference.

[0103] Examples of non-competitive NMDA-receptor antagonists that bindat the PCP site include, but are not limited to, ketamine,phencyclidine, dextromethorphan, dextrorphan, dexoxadrol, dizocilpine(MK-801), remacemide, thienylcyclohexylpiperidine (TCP),N-allylnormetazocine (SKF 10,047), cyclazocine, etoxadrol,(1,2,3,4,9,9a-hexahydro-fluoren-4a-yl)-methyl-amine (PD 137889);(1,3,4,9,10,10a-hexahydro-2H-phenanthren-4a-yl)-methyl-amine (PD138289); PD 138558, tiletamine, kynurenic acid, 7-chloro-kynurenic acid,and memantine; and quinoxalinediones, such as6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and6,7-dinitro-quinoxaline-2,3-dione (DNQX).

[0104] 4. N-methyl-D-aspartate Receptor Antagonists That Block The NMDAReceptor at the Polyamine or Zinc Binding Site and other NMDA-Receptorantagonists

[0105] As used herein the meaning of “NMDA-receptor antagonist”encompasses compounds that block the NMDA receptor at the polyaminebinding site, the zinc-binding site, and other NMDA-receptor antagoniststhat are either not classified herein according to a particular bindingsite or that block the NMDA receptor by another mechanism. Examples ofNMDA-receptor antagonists that bind at the polyamine site include, butare not limited to, spermine, spermidine, putrescine, and arcaine.Examples of assays useful to identify NMDA-receptor antagonists that actat the zinc or polyamine binding site are disclosed in U.S. Pat. No.5,834,465 (issued Nov. 10, 1998), hereby expressly incorporated byreference herein.

[0106] Other NMDA-receptor antagonists include, but are not limited to,amantadine, eliprodil, iamotrigine, riluzole, aptiganel, flupirtine,celfotel, levemopamil,1-(4-hydroxy-phenyl)-2-(4-phenylsulfanyl-piperidin-1-yl)-propan-1-one;2-[4-(4-fluoro-benzoyl)-piperidin-1-yl]-1-naphthalen-2-yl-ethanone (E2001);3-(1,1-dimethyl-heptyl)-9-hydroxyrnethyl-6,6-dimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol(HU-211);1-{4-[1-(4-chloro-phenyl)-1-methyl-ethyl]-2-methoxy-phenyl}-1H-[1,2,4]triazole-3carboxylicacid amide (CGP 31358); acetic acid10-hydroxy-7,9,7′,9′-tetramethoxy-3,3′-dimethyl-3,4,3′,4′-tetrahydro-1H,1′H-[5,5′]bi[benzo[g]isochromenyl]-4-ylester (ES 242-1);14-hydroxy-11-isopropyl-10-methyl-5-octyl-10,13-diaza-tricyclo[6.6.1.04,15]pentadeca-1,4,6,8(15)-tetraen-12-one;and 4,5-dioxo-4,5-dihydro-1H-benzo[g]indole-2,7,9-tricarboxylic acid(PQQ) and pharmaceutically acceptable salts thereof.

[0107] 5. Concentration of NMDA-Receptor Antagonist in Compositions ofthe Invention

[0108] The amount of NMDA-receptor antagonist in compositions of theinvention will vary according to the type and identity of theNMDA-receptor antagonist, the concentration and identity of theantidepressant, and the painful indiction treated. Dosages andconcentrations for a particular NMDA-receptor antagonist can beoptimized according to routine experiments using well-known pain models,for example, those described in J. Sawynok et al., 82 Pain 149 (1999)and J. Sawynok et al., 80 Pain 45 (1999).

[0109] In general, the amount of NMDA-receptor antagonist in thecompositions of the invention is within the range of from about 0.1percent to about 5 percent of the total weight of the composition, morepreferably, of from about 0.3 percent to about 0.5 percent of the totalweight of the composition.

[0110] D. The Lipophilic Component

[0111] The lipophilic component in the compositions of the invention canbe any waterinsoluble (hydrophobic) organic material or mixture ofmaterials that can form a stable emulsion comprising an antidepressantand an NMDA-receptor antagonist, suitable for intradermaladministration. Preferably, the lipophilic component comprises about 15%to about 40% by weight of the total composition weight, more preferably,about 20% by weight.

[0112] Suitable lipophilic components are well known in the art andinclude, but are not limited to, vegetable, nut, and seed oils, such asalmond oil, castor oil, coconut oil, corn oil, cotton seed oil, jojobaoil, linseed oil, grape seed oil, rape seed oil, mustard oil, olive oil,palm and palm kernel oil, peanut oil, safflower oil, sesame oil, soybeanoil, sunflower-seed oil, crambe oil, wheat germ oil, and cocoa butter;animal oils and fats, such as lanolin, tallow, lard, beef fat,butterfat, mink oil, and fish oils; hydrocarbon and petroleum oils, suchas petrolatum, mineral oil, and liquid paraffin; and higher fatty acidssuch as lauric acid, myristic acid, palmitic acid, stearic acid, behenicacid, oleic acid, 12-hydroxystearic acid, undecylenic acid, tall acid,lanolin fatty acid, isostearic acid, linoleic acid, and linolenic acid.Preferably, the lipophilic component is a petroleum oil, such aspetrolatum, mineral oil, or liquid paraffin, more preferably,petrolatum.

[0113] Preferably, the lipophilic component further comprises a“stiffening agent” (i.e., a hydrophobic material that is a solid at roomtemperature but melts within the temperature range of about 40° C. to80° C.) to provide a creamy feel to the compositions of the invention.The preferred amount of stiffening agent is about 1% to about 10% byweight of the total composition weight. Examples of suitable stiffeningagents include, but are not limited to, cetyl alcohol, cetyl esters wax,microcrystalline wax, paraffin, stearyl alcohol, lauryl alcohol, miraclealcohol, cetostearyl alcohol, white wax, yellow wax, bee wax, candelillawax, cotton wax, carnauba wax, bayberry wax, rice-bran wax. Cetylalcohol is the preferred stiffening agent.

[0114] Preferably, the lipophilic component further comprises ahydrophobic material that facilitates absorption of the antidepressantand the NMDA-receptor antagonist into the skin, referred to herein as a“lipophilic intradermal-penetration enhancer”. The preferred amount oflipophilic-intradermnal-penetration enhancer is about 1% to about 15% byweight of the total composition weight. Suitable lipophilic intradermalpenetration enhancers include isopropyl myristate, glycerol monolaurate,glycerol monooleate, glycerol monolinoleate, isopropyl isostearate,isopropyl linoleate, isopropyl myristate/fatty acid monoglyceridecombination, isopropyl myristate/ethanol/L-lactic acid combination,isopropyl palmitate, methyl acetate, methyl caprate, and methyl laurate.

[0115] Preferably, the lipophilic phase further comprises a hydrophobic(water-insoluble) surfactant. The preferred amount of hydrophobicsurfactant is about 2% to about 8% by weight of the total compositionweight. Hydrophobic surfactants are well known in the art; for example,but not limited to, emulsifying wax, polyoxyethylene acid,polyoxyethylene alcohol, glycerol monostearate, sorbitan tristearate,sorbitan monopalmitate, sorbitan sesquiloleate, and other sorbitan fattyacid esters.

[0116] E. The Surfactant System

[0117] The compositions of the invention comprise a surfactant tostabilize the emulsion. Surfactants can be cationic, nonionic, anionic,or amphoteric. For an extensive discussion on surfactants and emulsions,see Gillian M. Eccleston, Emulsions in 5 Encyclopedia of PharmaceuticalTechnology 137-184 (James C. Swarbrick & James C. Boylan eds. 1988). Foruse in the invention, the surfactant can be any intradermally-acceptablehydrophilic or hydrophobic material or mixture of materials capable ofstabilizing an oil-in-water type emulsion. One of skill in the art willreadily choose a suitable surfactant or surfactant mixture based on thehydrophilic-lipophilic balance (HLB) values of the surfactant and thelipophilic component. The preferred amount of surfactant is about 2% toabout 15% by weight of the total weight of the composition, morepreferably, about 10%.

[0118] The phrase “hydrophilic lipophilic balance” or “HLB”, as is wellknown in the art, refers to the numerical value assigned to a surfactantaccording to the method of Griffin, for the purpose of facilitatingsurfactant selection prior to emulsion preparation. For a detaileddiscussion of the HLB system and tables of numerical values see Griffin1 J. Soc. Cosmet. Chem. 311 (1949); 1 Remington: The Science andPractice of Pharmacy 286-289 (Alfonso R. Gennaro ed., 19th ed. 1995);Transdermal and Topical Drug Delivery Systems 542-546 (Tapash K. Ghoshet al. eds., 1997), all of which citations are hereby expresslyincorporated by reference herein.

[0119] While emulsion preparation is essentially a trial and errorpractice, in general, if an oil-in-water type emulsion is desired, theformulator should begin formulating with a surfactant system having anHLB value within the range of about 8 to 18 (±2). On the other hand, ifa water-in-oil type emulsion is desired, the formulator should beginformulating with a surfactant system having an HLB value within therange of 4 to 6 (±2).

[0120] Materials commonly used as hydrophobic components in emulsionsare assigned a “required HLB value”. The required HLB value is the HLBvalue that a surfactant or surfactant system must have to effectivelyemulsify a particular material. For example, to prepare a oil-in-watertype emulsion of a lipophilic material that has a required HLB value of10.5, a surfactant system that has an HLB of about 10.5 (±2) should beused.

[0121] Suitable surfactants having HLB values between 8-18 (±2) include,but are not limited to, sorbitan monolaurate, glycerol monostearate, PEG20 sobitan monolaurate, PEG sobitan monopalmitate, PEG 20 sorbitanmonostearate, PEG 20 sobitan monooleate, PEG 20 sobitan trioleate, PEG 8stearate, PEG 40 stearate, PEG-100 stearate, and other PEG stearates;PEG 4 lauryl ether, PEG 21 stearyl ether, PEG 2 oleyl ether.

[0122] In addition, mixtures of surfactants are suitable for use in theinvention. As a general rule, when mixtures of surfactants are used, theHLB value of the surfactant mixture should be within ±2 to the requiredHLB value for the lipophilic component (typically between 8 and 18(±2)). HLB values are algebraically additive making such calculationsrelatively simple. Suitable surfactant mixtures include, but are notlimited to sorbitan tristearate and PEG 20 sorbitan monostearate;sorbitan monopalmitate and PEG 20 sorbitan monopalminate; and sorbitansesquioleate and PEG 20 laurly ether.

[0123] F. Preservatives

[0124] In a preferred embodiment, the compositions of the inventionfurther comprise a preservative. In general, topical formulationsrequire preservation from microbial contamination that can effect thestability of the formulation and infect the user. When present in acomposition of the invention, the amount of preservative is preferablyfrom about 0.001% to about 1% by weight of the total composition weight,more preferably from about 0.01% to about 0.5% by weight. In someinstances, It is also advantageous to include an antioxidant to preservemedicaments and excipients present in topical formulations. Somemedicaments and excipients are oxygen labile and can undergo oxidation.When present in a composition of the invention, the amount ofantioxidant is preferably from about 0.001% to about 1% by weight of thetotal composition weight, more preferably from about 0.01% to about 0.5%by weight.

[0125] Examples of preservatives include, but are not limited to,quaternary amines, such as quaternium 15, benzalkonium chloride,cetrimide, benzethonium chloride; and imidizolidinyl urea; organicacids, such as sorbic acid, p-hydroxybenzoic acid, and benzoic acid;parabens, such as methyl paraben and propyl paraben; alcohols, such asbenzyl alcohol and isopropyl alcohol; phenols, such as triclosan,chlorhexidine, and thimerosal; hydantoin derivatives;chloromethylthiazoline; methylisothiazoline; phenyoxyethol; hexetidine;chlorohexydingluconate; and imidazolidinylurea. Preferably thepreservative is methyl paraben, propyl paraben, or a mixture thereof.

[0126] Examples of antioxidants include, but are not limited to,ascorbic acid and its esters, sodium bisulfite, sodium metabisulfite,thiourea, butylated hydroxytoluene, butylated hydroxyanisole,tocopherols, alkyl gallates, and chelating agents like EDTA and citricacid.

[0127] G. Anti-Foaming Agents

[0128] In a preferred embodiment, the compositions of the inventionfurther comprise an anti-foaming agent to facilitate manufacture.Anti-foaming agents dissipate foam by destabilizing the air-liquidinterface and allow liquid to drain away from air pockets. When presentin a composition of the invention, the amount of anti-foaming agent ispreferably from about 0.01% to about 1% by weight of the totalcomposition weight, more preferably from about 0.1% to about 0.5% byweight.

[0129] Examples of anti-foaming agents include simethicone, dimethicone,ethanol, and ether. Preferably, the anti-foaming agent is simethicone.

[0130] H. Emollients, Humectants, and Skin Protectants

[0131] In a preferred embodiment, the compositions of the inventionfurther comprise an emollients, a humectants, or a skin protectant,preferably a humectant to soothe and hydrate the skin. When present in acomposition of the invention, the amount of humectant, skin protectant,or emollient is preferably from about 1% to about 10% by weight of thetotal composition weight, more preferably from about 2% to about 5% byweight.

[0132] Examples of humectants include, but are not limited to, glycerin,sorbitol, polyethylene glycols, urea, propylene glycol, 1,3-butyleneglycol, ethanol, and isopropanol. In a preferred embodiment sorbitol isthe humectant, preferably, 70% aqueous sorbitol solution. Examples ofemollients include, but are not limited to, cholesterol and glycerol.Examples of skin protectants include, but are not limited to, vitamin Eoil, allatoin, glycerin, zinc oxide, vitamins A, B (e.g. biotin andpantothenic acid), C, E, F, H, and P, and esters thereof.

[0133] I. Penetration Enhancers

[0134] In another embodiment, the compositions of the invention canfurther comprise a penetration enhancer. When present in a compositionof the invention, the amount of penetration enhancer is preferably fromabout 1% to about 10% by weight of the total composition weight, morepreferably from about 2% to about 5% by weight.

[0135] Penetration enhancers can be included in the compositions of theinvention to optimize transfer of the antidepressant and theNMDA-receptor antagonist through the stratum comeum and into the dermisto provide a local effect. For a discussion of use of penetrationenhancers in topical formulations see generally, PercutaneousPenetration Enhancers (Eric W. Smith & Howard I. Maibach eds. 1995);Ghosh, T. K. et al. 17 Pharm. Tech. 72 (1993); Ghosh, T. K. et al. 17Pharm. Tech. 62 (1993);Ghosh, T.K. et al. 17 Pharm. Tech. 68 (1993), allof which citations are hereby incorporated herein by reference. Thepenetration enhancer should be pharmacologically inert, non-toxic, andnon-allergenic, have rapid and reversible onset of action, and becompatible with the compositions of the invention.

[0136] Examples of penetration enhancers include, but are not limitedto, transcutol P, ethyl alcohol, isopropyl alcohol, lauryl alcohol,salicylic acid, octolyphenylpolyethylene glycol, polyethylene glycol400, propylene glycol, N-decylmethylsulfoxide, DMSO and the azacyclocompounds, as disclosed in U.S. Pat. Nos. 4,755,535; 4,801,586;4,808,414; and 4,920,101, all of which patents are hereby expresslyincorporated herein by reference. Preferably, the penetration enhanceris transcutol P.

[0137] J. Other Local Anesthetics

[0138] The compositions of the invention can further comprise one ormore additional local anesthetics besides an antidepressant and anNMDA-receptor antagonist. As used herein, the term “local anesthetic”means any compound or composition that provides local numbness oranalgesia or any drug that provides a regional blockage of nociceptivepathways (afferent and/or efferent). The local anesthetic can be anylocal anesthetic known or to be developed. When present in a compositionof the invention, the amount of local anesthetic is preferably fromabout 0.1% to about 10% by weight of the total composition weight.

[0139] Examples of local anesthetics suitable for use with the inventioninclude sodiumchannel blockers. Sodium-channel blockers, such aslidocaine prevent the generation and conduction of nerve impulses bydecreasing or preventing the large transient increase in the ermeabilityof excitable membranes to Na+. Examples of sodium-channel blockersinclude, but are not limited to, ambucaine, amolanone, amylcaine,benoxinate, benzocaine, etoxycaine, biphenamine, bupivacaine, butacaine,butamben, butanilicaine, butethamine, butoxycaine, carticaine,chloroprocaine, cocaethylene, cocaine, cyclomethycaine, dibucaine,dimethisoquin, dimethocaine, diperodon, dyclonine, ecogonidine,ecogonine, euprocin, fenalcomine, formocaine, hexylcaine,hydroxyteteracaine, isobutylp-aminobenzoate, leucinocaine, levoxadrol,lidocaine, mepivacaine, meprylcaine, metabutoxycaine, methyl chloride,myrtecaine, naepaine, octacaine, orthocaine, oxethazaine,parenthoxycaine, phenacaine, phenol, piperocaine, piridocaine,polidocanol, pramoxine, prilocaine, procaine, propanocaine,proparacaine, propipocaine, propoxycaine, pseudococaine, pyrrocaine,ropivacaine, salicyl alcohol, tetracaine, tolycaine, trimecaine,zolarmine, or pharmaceutically-acceptable salts thereof, or mixturesthereof. Preferred sodium-channel blockers, include lidocaine, procaine,bupivacaine, prilocaine, mepivacaine, etidocaine, ropivacaine,dibucaine, and pharmaceutically-acceptable salts thereof and mixturesthereof. The most preferred local anesthetic is lidocaine andpharmaceutically acceptable salts thereof.

[0140] Opioids, such as morphine are known to have local-anestheticproperties when topically administered in mammals. See, for example,U.S. Pat. No. 5,948,389 (issued Sep. 7, 1999) and Christoph Stein &Alexander Yassouridis 71 Pain 119 (1997).

[0141] As used herein the term “opioid” means all agonists andantagonists of opioid receptors, such as mu (μ), kappa (κ), and delta(δ) opioid receptors and subtypes thereof. For a discussion of opioidreceptors and subtypes see Goodman & Gilman's the Pharmacological Basisof Therapeutics 521-525 (Joel G. Hardman et al. eds., 9th ed. 20 1996),hereby expressly incorporated herein by reference. The opioid can be anyopioid receptor agonist or antagonist known or to be developed.Preferred opioids interact with the μ-opioid receptor, the K-opioidreceptor, or both. Preferably, the opioid is an opioid-receptor agonist.

[0142] Examples of suitable opioids include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,benzitramide, nor-binaltorphimine, bremazocine, buprenorphine,butorphanol, clonitazene, codeine, CTOP, DAMGO, desomorphine,dextromoramide, dezocine, diampromide, dihydrocodeine, dihydrocodeineenol acetate, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, diprenorphine,DPDPE, eptazocine, ethoheptazine, ethylketocyclazocine,ethylmethylthiambutene, etonitazene, etorphine, fentanyl, hydrocodone,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levorphanol, lofentanil, loperamide, meperidine, meptazinol,metazocaine, methadone, metopon, morphine, myrophine, nalbuphine,naltrindole, benzoylhydrazone, naltrexone, narceine, nicomorphine,norlevorphanol, normethadone, nornorphine, norpipanone, opium,oxycodone, oxymorphone, papaveretum, papaverine, pentazocine,phenadoxone, phenazocine, phenoperidine, piminodine, pirtramide,proheptazine, promedol, propiram, propoxyphene, remifentanil,spiradoline, sufentanil, tilidine, U50,488, and U69,593, amiphenazole,cyclazocine, levallorphan, nalmefene, nalorphine, naloxone, andnaltrexone or pharmaceutically-acceptable salts thereof, or mixturesthereof.

[0143] Examples of peptide opioids include, but are not limited to,Tyr-Gly-Gly-Phe-Leu ([Leu⁵]enkephalin), Tyr-Gly-Gly-Phe-Met([Met⁵]enkephalin),Tyr-Gly-Gly-Phe-Leu-Arg—Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln(DynorphinA), Tyr-Gly-Gly-Phe-Leu-Arg—Arg-Gln-Phe-Lys-Val-Val-Thr(Dynorphin B), Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys (α-Neoendorphin),Tyr-Gly-Gly-Phe-Leu-Arg-Lsy-Tyr-Pro (β-Neoendorphin),Tyr-Gly-Gly—Phe-Met-Thr-Ser-Glu-Lys-Ser-Gln-Thr-Pro-Leu-Val-Thr-Leu-Phe-Lys-Asn-Ala-Ila-Ile-Lsy—Asn-Ala-Tyr-Lys-Lys-Gly-Glu(β_(h)-Endorphin), [D-Ala²,MePhe⁴Gly(ol)⁵]enkephalin (DAMGO),[D-Pen²,D-Pen⁵]enkephalin (DPDPE), [D-Ser²,Leu⁵]enkephalin-Thr⁶ (DSLET),[D-Ala²,D-Leu⁵]enkephalin (DADL),D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH₂(CTOP),[D-Ala²,N-MePhe⁴,Met(O)⁵-ol]enkephalin (FK-33824),Tyr-D-Ala-Phe-Asp-Val-Val-Gly—NH₂ ([D-Ala²]Deltorphin 1),Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH₂ ([D-Ala²Glu⁴]Deltorphin (DeltorphinII)), Tyr-Pro-Phe-Pro-NH² (Morphiceptin), Tyr-Pro-MePhe-D-Pro-NH²(PL017), [D-Ala²,Leu⁵,Cys⁶]enkephalin (DALCE) orpharmaceutically-acceptable salts thereof, or mixtures thereof.Preferred opioids include morphine, loperamide, and loperamidederivatives such as those disclosed in U.S. Pat. Nos. 5,763,445;5,981,513; 5,869,521; 5,744,458; 5,760,023; 5,798,093; 5,849,762;5,811,078; 6,004,964; 5,962,477; 5,688,955; 5,888,494; 5,646,151; and5,667,773 or pharmaceutically-acceptable salts thereof, or mixturesthereof, all of which patents are hereby expressly incorporated hereinby reference. The most preferred opioid is morphine or apharmaceutically-acceptable salt thereof.

[0144] Other agents with local-anesthetic properties include analgesics,such as nonsteroidal anti-inflammatories (“NSAIDs”), see, for example,Transdermal and Topical Drug Delevery Systems 87-93 (Tapash K. Ghosh etal. eds., 1997). Examples of non-narcotic analgesics withlocal-aesthetic properties include, but are not limited to,acetylsalicylic acid, ketoprofen, piroxicam, diclofenac, indomethacin,and ketorolac.

[0145] In yet another embodiment of the current invention, agents may beincluded in the compositions of the invention to prolong thelocal-anesthetic effect, such as, a glucocorticosteroid (see, forexample, U.S. Pat. No. 5,922,340, incorporated herein by reference) or avasoconstrictor, such as a catecolamine.

[0146] K. Other Excipients

[0147] The compositions of the invention can further comprise one ormore additional ingredients, such as one or more thickening agents,medicinal agents or pharmaceuticals, bioadhesive polymers, inertcarriers, lipid absorbents, viscosity stabilizers, chelating agents,buffers, anti-fading agents, stabilizers, moisture absorbents,fragrances, colorants, film-forming materials, and refatting agents,etc. One of skill in the art will readily be able to choose suchadditional excipients based on the physical and chemical propertiesdesired in the final topical formulation. Of course, a single excipientmay have multiple functions and properties.

[0148]1. Thickening Agents

[0149] The compositions of the invention can further comprise one ormore thickening agents. Thickening agents are used to increase viscosityand improve bioadhesive properties. When present in a composition of theinvention, the amount of thickening agent is preferably from about 1% to10% by weight of the total composition weight, more preferably fromabout 2% to about 5% by weight.

[0150] Examples of thickening agents include, but are not limited to,cellulose, hydroxypropyl cellulose, methyl cellulose, polyethyleneglycol, sodium carboxymethyl cellulose, polyethylene oxide, xanthan gum,guar gum, agar, carrageenan gum, gelatin, karaya, pectin, andlocust-bean gum, aliginic acid, bentonite carbomer, povidone, andtragacanth.

[0151] 2. Medicinal Agents

[0152] The compositions of the invention can include medicinal agents ortheir pharmaceutically acceptable salts. One of skill in the art canreadily choose a medical agent to incorporate into the compositions ofthe invention and its appropriate concentration depending on theindication and desired effect. Examples of medicinal agents include, butnot limited to, antifungals such as ciclopirox, chloroxylenol,triacetin, sulconazole, nystatin, undecylenic acid, tolnaftate,miconizole, clotrimazole, oxiconazole, griseofulvin, econazole,ketoconozole, and amphotericin B; antibiotics, such as mupirocin,erthromycin, clindamycin, gentamicin, polymyxin, bacitracin, and silversulfadiazine; antiseptics, such as iodine, povidine-iodine, benzalkoniumchloride, benzoic acid, chlorhexidine, nitrofurazone, benzoyl peroxide,hydrogen peroxide, hexachlorophene, phenol, resorcinol, andcetylpyridinium chloride; and anti-inflammatories, such ashydrocortisone, prednisone, triamcilolone, betamethasone, dexamethasone.

[0153] 3. Bioadhesive Polymers

[0154] The compositions of the invention can include one or morebioadhesive polymers. Bioadhesive polymers are also useful in thepresent invention to hydrate the skin and enhance its permeability.Bioadhesive polymers can also function as thickening agents. Examples ofbioadhesive polymers include, but are not limited to, pectin, alginicacid, chitosan, hyaluronic acid, polysorbates, such as polysorbate−20,−21, −40, −60, −61, −65, −80, −81, −85; poly(ethyleneglycol), such asPEG−7, −14, −16, −18, −55, −90, −100−135, −180, −4, −240, −6, −8, −9,−10, −12, −20, or −32; oligosaccharides and polysaccharides, such asgellan, carrageenan, xanthan gum, gum Arabic, and dextran; celluloseesters and cellulose ethers; modified cellulose polymers, such ascarboxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxyethyl ethylcellulose; polyether polymers andoligomers, such as polyoxyethylene; condensation products ofpoly(ethyleneoxide) with various reactive hydrogen containing compoundshaving long hydrophobic chains (e.g. aliphatic chains of about 12 to 20carbon atoms), for example, condensation products of poly(ethyleneoxide) with fatty acids, fatty alcohols, fatty amides, polyhydricalcohols; polyether compounds, such as poly(methyl vinyl ether),polyoxypropylene of less than 10 repeating units; polyether compounds,such as block copolymers of ethylene oxide and propylene oxide; mixturesof block copolymers of ethylene oxide and propylene oxide with otherexcipients, for example, pluronic lethicin organogel (see 1International Journal of Pharmaceutical Compounding 71 (1997));poly(vinyl alcohol); polyacrylamide; hydrolyzed polyacrylamide;poly(vinyl pyrrolidone); poly(methacrylic acid); poly(acrylic acid) orcosslinked polyacrylic acid, such as carbomer, i.e., a homopolymer ofacrylic acid crosslinked with either an allyl ether of pentaerythritol,an allyl ether of sucrose, or an allyl ether of propylene (e.g.,Acrisint® 400, 410, or 430 commercially available from 3V Inc.Weehawkin, N.J.); Orabase® (i.e., a mixture of gelatine, pectin andsodium carboxymethyl cellulose in a plasticized hydrocarbon gel,commercially available from Hoyt laboratories, Needhm, Me.); Carafate®(sulfated sucrose and aluminum hydroxide, commercially available fromMarion Laboratories, Inc., Kansas City, Mo.). The block copolymers ofethylene oxide and propylene oxide are particularly preferred.

[0155] L. Methods of Manufacture

[0156] The compositions of the invention is prepared according tostandard methods, well known in the art, for preparing oil-in-wateremulsions for topical administration. For example, the methods recitedin 1 Remington: The Science and Practice of Pharmacy 289 (Alfonso R.Gennaro ed., 19th ed. 1995), hereby expressly incorporated herein byreference, can be used. Also, Example preparations are recited in theExample section below.

[0157] For example, the components can be separated into those that arewater soluble and those that are oil soluble. The water-solublecomponents can be mixed together in one vessel to form a solution andthe oil-soluble components can be mixed together in a separate vesseland heated (e.g., 70° C. to 80° C.) to form a solution. The twosolutions can then be mixed and the mixture allowed to cool. This methodrequires nothing more than two beakers and a heating apparatus.Homogenation is achieved using a high-shear rate blender or othersuitable apparatus. The appropriate droplet size is achieved by standardadjustment of the shear rate during high-speed mixing followed bydroplet size analysis as described in 1 Remington: The Science andPractice of Pharmacy 282-283 (Alfonso R. Gennaro ed., 19th ed. 1995) andAllen & Terence, Particle Size Measurement 483 (4th ed. 1990, both orwhich citations are hereby expressly incorporated herein by reference.Suitable equipment and methods for preparing emulsions and compositionsof the invention, such as high-shear rate blenders are described in 2Remington: The Science and Practice of Pharmacy 1509-1515 (Alfonso R.Gennaro ed., 19th ed. 1995), hereby expressly incorporated herein byreference. Methods for preparation of emulsions for topicaladministration, suitable for preparing compositions of the invention,are also described in Bernard Idson, Pharmaceutical Emulsions in 1Pharmaceutical Dosage Forms: Disperse Systems 199 (Herbert A. Liebermanet al. eds. 1988), hereby expressly incorporated herein by reference.

[0158] The compositions of the invention are then packaged and storedaccording to wellknown methods. For example, see the packagingprocedures described in 1 Remington: The Science and Practice ofPharmacy 390-391 (Alfonso R. Gennaro ed., 19th ed. 1995), herebyincorporated herein by reference. If desired, the compositions of theinvention can be sterilized according to well-known methods, forexample, the methods described in 2 Remington: The Science and Practiceof Pharmacy 1463-1486 (Alfonso R. Gennaro ed., 19th ed. 1995), herebyincorporated herein by reference.

[0159] M. Methods of Administration

[0160] 1. Topical Application

[0161] The compositions of the invention can be topically administeredto intact skin by a medical professional or by the patient by simplemechanical rubbing into the application site. In applying thesecompositions to the skin, for maximum effectiveness and increasedabsorption, the area to which the composition is to be administered isfirst cleansed with an astringent, such as a standard commercialantiseptic or alcohol. The area is then allowed to dry for a fewseconds. Next, the composition of the invention is rubbed on to thecomplete target area of the skin (the painful area) and gently, butfirmly, massaged in with the fingertips until all visible gel or creamhas been absorbed.

[0162] After application of a composition of the invention, theapplication site can be covered with a dressing. The term “dressing”, asused herein, means a covering designed to protect a previously applieddrug formulation. “Dressing” includes coverings such as a bandage, whichmay be porous or non-porous and various inert coverings, e.g., a plasticfilm wrap or other non-absorbent film. The term “dressing” alsoencompasses non-woven or woven coverings, particularly elastomericcoverings, which allow for heat and vapor transport. These dressingsallow for cooling of the pain site, which provides for greater comfort.In another embodiment, a composition of the invention can beincorporated into a dressing, which dressing is then applied to the skinor painful area.

[0163] 2. Administration via an Intradermal Patch In one embodiment ofthe current invention, the compositions of the invention are containedin a patch that is applied adjacent to the area of skin to be treated.As used herein a “patch” comprises at least a composition of theinvention and a covering layer, such that, the patch can be placed overthe area of skin to be treated. Preferably, the patch is designed tomaximize drug delivery through the stratum comeum and into the epidermisor dermis, and to minimize absorption into the circulatory system,reduce lag time, promote uniform absorption, and reduce mechanicalrub-off.

[0164] Preferably, the patch components resemble the viscoelasticproperties of the skin and conform to the skin during movement toprevent undue shear and delamination.

[0165] Patches comprising the compositions of the invention haveadvantages over conventional methods of administration. One advantage isthat the dose is controlled by the patch's surface area. Otheradvantages of patches are constant rate of administration, longerduration of action (the ability of to adhere to the skin for 1, 3, 7days or longer); improved patient compliance, non-invasive dosing, andreversible action (i.e., the patch can simply be removed).

[0166] Examples of patches suitable for use with compositions of theinvention include (1) the matrix-type patch; (2) the reservoir-typepatch; (3) the multi-laminate drug-in-adhesive type patch; (4) themonolithic drug-in-adhesive type patch; and (5) hydrogel patch; seegenerally Ghosh, T. K.; Pfister, W. R.; Yum, S. I. Transdermal andTopical Drug Delivery Systems, Interpharm Press, Inc. p. 249-297, herebyexpressly incorporated herein by reference). These patches are wellknown in the art and available commercially.

[0167] In one embodiment, a composition of the invention is contained ina reservoir-type patch. The reservoir-type patch is characterized by abacking film coated with an adhesive and a reservoir compartmentcomprising a composition of the invention (see, for example, U.S. Pat.No. 4,615,699, hereby expressly incorporated herein by reference. Theadhesive coated backing layer extends around the reservoir's boundariesto provide a concentric seal with the skin and hold the reservoiradjacent to the skin.

[0168] In one embodiment, a composition of the invention is contained ina drug-inadhesive or hydrogel patch. The monolithic drug-in-adhesivepatch design is characterized by the inclusion of the drug formulationin the skin contacting adhesive layer, a backing film and preferably, arelease liner. The adhesive functions both to release the anesthetic andadhere the anesthetic matrix to the skin. The drug-in-adhesive systemdoes not require an adhesive overlay and thus the patch size isminimized. Also, drug-in-adhesive type patches are thin and comfortable(e.g., U.S. Pat. No. 4,751,087, hereby incorporated herein byreference).

[0169] The multi-laminate drug-in-adhesive patch design furtherincorporates additional semi-permeable membrane between two distinctdrug-in-adhesive layers or multiple drugin-adhesive layers under asingle backing film (Peterson, T. A. and Dreyer, S. J. Proceed. Intern.Symp. Control. Rel. Bioact. Mater. 21: 477-478, incorporated herein byreference).

[0170] Semi permeable membranes, useful with the reservoir ormulti-laminate patch, include thin non-porous ethylene vinyl acetatefilms or thin microporous films of polyethylene employed inmicrolaminate solid state reservoir patches.

[0171] Adhesives for use with the drug-in-adhesive type patches are wellknown in the art and selection is readily accomplished by an ordinarypractitioner. Three basic types commonly used are polyisobutylenes,silicones, acrylics, and hydrogels. Adhesives useful in the presentinvention can function under a wide range of conditions, such as, highand low humidity, bathing, sweating etc. Preferably the adhesive is acomposition based on natural or synthetic rubber, polyacrylate,polyvinylacetate, polybutylacrylate, polymethylacrylate,polydimethylsiloxane, and hydrogels (e.g., high molecular weightpolyvinylpyrrolidone, oligomeric polyethylene oxide, or a mixturethereof). The most preferred is polyacrylate and hydrogels. The mostpreferred adhesives are hydrogels and polyacrylates. In one embodiment,the hydrogel is electron-beam cross-linked polyvinylpyrrolidone (“PVP”)where the PVP is of an average molecular weight of about 500,000 Daltonsto about 2,000,000 Daltons, preferably, about 900,000 Daltons to about1,500,000 Daltons. Exemplary PVP-hydrogels for use in the invention aredescribed in WO 93/10163 (published May 27, 1993) page 12, line 24through page 13, line 3; U.S. Pat. No. 4,989,607 column 13, lines 10-25;EP 0 107 376 (published Feb. 5, 1984) page 19, lines 10-30; D. Darwis 42Radiat. Phys. Chem. 907 (1993); and Olgun Guven & Murat Sen 32 Polymer2491 (1991), all of which citations are hereby expressly incorporatedherein by reference.

[0172] Suitable release liners include but are not limited to occlusive,opaque, or clear polyester films with a thin coating of pressuresensitive release liner (e.g., silicone-fluorsilicone, andperfluorcarbon based polymers.

[0173] Backing films may be occlusive or permeable and are derived fromsynthetic polymers like polyolefin oils polyester, polyethylene,polyvinylidine chloride, and polyurethane or from natural materials likecotton, wool, etc. Occlusive backing films, such as syntheticpolyesters, result in hydration of the outer layers of the stratumcomeum while non-occlusive backings allow the area to breath (i.e.,promote water vapor transmission from the skin surface). More preferablythe backing film is an occlusive polyolefin foil (Alevo, Dreieich,Germany). The polyolefin foil is preferably about 0.6 to about 1 mmthick.

[0174] In general, the composition of the invention will comprise fromabout 0.5 percent to about 40 percent by weight of the patch, preferablyfrom about 10 percent to about 30 percent, more preferably from about 15percent to about 25 percent, and most preferably from about 18 percentto about 22 percent by weight of the patch.

[0175] The Patches for use with compositions of the invention can bemanufactured, packaged, stored and labeled according to standardprocedures. For example, see the procedures described in Bova et al.,Product Development and Technology Transfer for Transdermal TherapeuticSystems in Transdermal Controlled Systemic Medications 379-396 (Y. W.Chien ed. 1987); J. W. Dohner, Development of Processes and Equipmentfor Rate Controlled Transdermal Therapeutic Systems in TransdermalControlled Systemic Medications 349-364 (Y. W. Chien ed. 1987); H-M Wolfet al., Development of Processes and Technology for Adhesive-TypeTransdermal Therapeutic Systems in Transdermal Controlled SystemicMedications 365-378 (Y. W. Chien ed. 1987), all of which citations arehereby incorporated herein by reference.

[0176] 3. Dosage

[0177] Selection of the appropriate dosage for the application site isan important consideration. The rate of intradermal anestheticadministration from the topical formulation or patch is a function ofskin permeability, and skin permeability has been shown to vary betweenanatomical sites depending on the thickness of the stratum comeum. Forexample, the permeability, in general, increases in order from planterfoot arch, lateral ankle, palm, ventral forearm, dorsal forearm, back,chest, thigh, abdomen, scalp, axilla, forehead, and scrotum; see R. C.Wester. & H. I. Maibach Regional variation in Percutaneous Absorption inPercutaneous Absorbtion, Mechanism, Methodology, Drug Delevery 111-119(R. L. Bronaugh & H. I. Maibach eds., 2nd ed. 1989), hereby expresslyincorporated herein by reference. Of course, the dosages and dosingfrequency will be determined by a trained medical professional and willdepend upon many factors such as application site and size and theseverity of the indication.

[0178] With gels, creams, or ointments, typically 1 to 4 applicationsare required per day. Generally, about 0.5 g/cm² of skin area to about 5g/cm², preferably 1 g/cm² to about 2 g/cm² of a composition of theinvention is administered to and around the application site. Afteradministration, if desired, the area can be covered with a dressing.

[0179] When a patch is used to administer a composition of theinvention, the dosage to achieve pain relief is determined by the activesurface area of the medicated portion of the patch in direct contactwith the skin. Several dosage strengths are advantageous depending uponthe severity of the wound. In general, a physician can begin dosing witha low or intermediate strength patch and then, depending upon theeffectiveness, adjust the dosage up or down by prescribing a patch ofhigher or lower active concentration or a patch of larger or smallersurface area, or, in some cases, multiple patches. In general, thecomposition of the invention will comprise from about 0.5 percent toabout 20 percent by weight of the patch, preferably from about 5 percentto about 25 percent by weight of the patch. For matrix(drug-in-adhesive) type patches, the compositions of the invention willcomprise from about 0.5 percent to about 20 percent by weight of thepatch. For patches comprising a hydrogel, the compositions of theinvention will comprise from about 0.5 percent to about 10 percent byweight of the patch. Fresh patches may be administered multiple timesper day, but, preferably, a fresh patch is administered about every 18to about every 48 hours, more preferably daily.

[0180] The present invention and its many attendant advantages will beunderstood from the foregoing description and it will be apparent thatvarious changes in form, construction and arrangement of the partsthereof may be made without departing from the spirit and scope of theinvention or sacrificing all of its material advantages, the formhereinbefore described are merely exemplary embodiments thereof.

VI. EXAMPLES

[0181] All reagents used in the Examples below are commerciallyavailable from standard sources, for example from, Spectrum LaboratoryProducts, Inc. Gardena, Calif. Amitriptyline hydrochloride was purchasedfrom Spectrum Laboratory Products, Inc. Ketamine hydrochloride waspurchased from Medisca, Inc., Plattsburg, N.Y. As used throughout theExamples, “high-strength compositions” refer to compositions comprisingabout 2% ketamine and about 4% amitriptyline, and “low-strengthcompositions” refer to compositions comprising about 0.5% ketamine andabout 1% amitriptyline.

Example 1 Compositions A and B of the Invention Comprising Amitriptylineand Ketamine

[0182] Compositions A and B are compositions according to the invention.The topical amitriptyline-ketamine cream compositions A and B comprisingamitriptyline hydrochloride and ketamine hydrochloride were formulatedaccording to the following procedure using the component weights listedin Table 1. The oil-phase components are detailed in Table 2. TABLE 1Compositions A and B: High- and Low-strength Ketamine-AmitriptylineCompositions of the Invention Compositions A Composition B (highstrength) (low strength) component weight weight % weight weight %ketamine 138 g 2.3% 34.8 g 0.58% hydrochloride amitriptyline 270 g 4.5%67.8 g 1.13% hydrochloride methyl paraben 12 g 0.2% 12 g  0.2% propylparaben 1.2 g 0.02%  1.2 g 0.02% sorbitol (70% solution) 426 g 7.1% 426g  7.1% PEG-100 stearate 390 g 6.5% 390 g  6.5% simethicone 6 g 0.1% 6 g 0.1% Oil Phase* 1200 g  20% 1200 g   20% water 3558 59.3%  3864 64.4%

[0183] TABLE 2 The Oil-Phase Components of Compositions A and B in Table1 Above component weight weight % cetyl alcohol 156 g 13% isopropylmyristate 528 g 44% glycerol stearate 264 g 22% petrolatum 252 g 21%

[0184] Aqueous-Phase Solution: Sorbitol solution, water, and PEG-100stearate, were added to a Groen kettle (Model “TDB/8-20 CFC”, GroenDivision, Dover Corporation, Elk Grove Village, Ill.). The kettle has aself-contained water jacket. The temperature was maintained within therange of about 70° C. to about 80° C. The kettle was covered, and themixture was heated and stirred. When a solution resulted, themethylparaben, ketamine hydrochloride, and amitriptyline hydrochloridewere added. Stirring and heating continued until all ingredients weredissolved.

[0185] Oil-Phase Solution: The cetyl alcohol, isopropyl myristate,glycerol stearate and petrolatum were added to a stainless-steelcontainer immersed in a hot water bath. The water-bath temperature wasmaintained in the range of 70° C. to 80° C. using a hot-plate. Thesolution was heated and stirred (Lab-Stirrer, Model LR 400 C, FisherScientific Inc., Pittsburgh, Pa.) until a homogenous liquid resulted.Propylparaben was then added and stirring and heating continued untilthe propylparaben was completely dissolved.

[0186] The oil phase (70° C.) was slowly poured into the aqueous phase(70° C.) and the resulting mixture was stirred for 10 minutes using thekettle-stirring device. The kettlestirring device was then disassembledand the mixture was emulsified using a high-shear homogenizer (PowerGenHomogenizer, Model 700D, Fisher Scientific Inc., Pittsburgh, Pa.) for 15minutes. The kettle stirring device was then reassembled to stir theresulting emulsion while the hot water in the kettle jacket was replacedwith ice water to cool the emulsion. After the emulsion temperaturedropped below 40° C., simethicone was added and the emulsion was thenmixed for another 15 minutes using the kettle-stirring device. A GrisonaMA filling machine (NAG Nahma AG, Unterageri, Austria) was used to fillthe emulsion into 60 gram aluminum tubes (Peerless Tube Company,Bloomfield, N.J.).

[0187] The oil-phase-droplet diameters (weight mean diameter) weremeasured via laser-light diffraction (Malvern Mastersizer S LaserDiffractor, Malvern Instruments Ltd, Malvem, UK). Prior to the analysis,emulsion samples were dispersed in a 6.5% solution of PEG-100 stearatein purified water. Sample refractive index and carrier-fluid refractiveindex were set at 1.5295 and 1.33, respectively. The default setting forthe Presentation and Analysis Model was “OHD” and “Polydisperse”.Droplet size was determined to be in the range of 0.2 microns to 100microns, the mean-droplet size was 0.34 microns.

Example 2 Compositions C and D of the Invention Comprising Amitriptylineand Ketamine and Transcutol-P as a Permeation Enhancer

[0188] The procedure described above in Example 1 above was used toprepare amitriptyline-ketamine emulsion compositions C and D, whichfurther contained the permeation enhancer Transcutol-P (ethoxydiglycol,commercially available, for example, from Gattefosse, Westwood, NJ).Transcutol-P was blended together with water, sorbitol solution, andPEG-100 stearate during formulation of the aqueous phase. TABLE 3Compositions C and D: High- and Low-Strength Ketamine- AmitriptylineCompositions of the Invention Comprising a Permeation Enhancer(Transcutol-P) Compositions C Composition D (high strength) (lowstrength) component weight weight % weight weight % ketamine 138 g 2.3%34.8 g 0.58% hydrochloride amitriptyline 270 g 4.5% 67.8 g 1.13%hydrochloride methyl paraben 12 g 0.2% 12 g  0.2% propyl paraben 1.2 g0.02%  1.2 g 0.02% transcutol-P 300 g   5% 300 g   5 sorbitol (70%solution) 426 g 7.1% 426 g  7.1% PEG-100 stearate 390 g 6.5% 390 g  6.5%simethicone 6 g 0.1% 6 g  0.1% Oil Phase* 1200 g  20% 1200 g   20% water3258 g 54.3%  3564 59.4%

Example 3 Topical Pluronic-Gel Formulations E and F ComprisingAmitriptyline and Ketamine with a Permeation Enhancer (Transcutol-P)

[0189] Topical pluronic gel compositions E and F were prepared forskin-permeation rate comparison to compositions of the invention A-D.The formulation and component weights of compositions E and F are shownin Table 4.

[0190] Amitriptyline hydrochloride and ketamine hydrochloride weredissolved in the water in a glass beaker. Methylparaben andpropylparaben were mixed with Transcutol-P in a separate beaker. TheTranscutol-P solution containing the methylparaben and propylparaben waspoured into the amitriptyline hydrochloride/ketamine hydrochloridesolution. A glass beaker containing the above solution was then placedinside a ice bath to cool the solution to approximately 5° C. PluronicF127 was added to the solution with continuous mixing (Lab-Stirrer,Model LR 400 C, Fisher Scientific Inc., Pittsburgh, Pa.) forapproximately 12 hours until a clear solution resulted. Whilemaintaining the temperature just below about 10° C., the clear solutionwas filled into aluminum tubes. When the solution temperatureequilibrated to room temperature, it transformed into a clear gel. TABLE4 Compositions E and F: High- and Low-Strength Pluronic-Gel FormulationsComprising Amitriptyline and Ketamine with a Permeation EnhancerCompositions E Composition F (high strength gel (low strengthformulation) Gel formulation) component weight weight % weight weight %Amitriptyline HCl 4.5 4.5% 1.13 1.13% Ketamine HCl 2.3 2.3% 0.58 0.58%Methylparaben 0.2 0.2% 0.2  0.2% Propylparaben 0.02 0.02%  0.02 0.02%Transcutol-P 2.0 2.0% 2.0  2.0% Pluronic F127 30.0 30.0%  30.0 30.0%Water 61.0  61% 66.1 66.1%

Example 4 Topical Pluronic-Lecithin Gel Formulations G and H ComprisingAmitriptyline and Ketamine with a Permeation Enhancer (transcutol-P)

[0191] Pluronic-lecithin-gel (PLO) compositions G and H, which furthercontained the permeation enhancer transcutol-P, were prepared forskin-permeation rate comparison to compositions of the invention A-D.The formulation and component weights of compositions G and H are shownin Table 5 below. The indicated amounts of amitriptyline hydrochloride,transcutol-P, ketamine hydrochloride, and pluronic solution were placedinto a 200 ml glass beaker and maintained at approximately 5° C. usingan ice bath and stirred using a mechanical mixer (Lab-Stirrer, Model LR400 C, Fisher Scientific Inc., Pittsburgh, Pa.) until a solutionresulted.

[0192] Methylparaben, propylparaben, vitamin E, lecithin, and isopropylmyristate were mixed in a separate vessel using a glass mortar & pestlevia trituration until a solution resulted. The two solutions werecombined in the glass mortar and mixed under vigorous trituration forapproximately 5 minutes. The finished product was a smooth gel with ayellow tinge. TABLE 5 Compositions G and H: Pluronic-Lecithin GelFormulations Comprising Amitriptyline and Ketamine with a PermeationEnhancer (Tanscutol-P) Composition G Composition H (high strength gel(low strength Gel formulation) formulation) component weight weight %weight weight % Amitriptyline HCl 4.5 4.5% 1.13 1.13%  Ketamine HCl 2.32.3% 0.58 0.58%  Methylparaben 0.2 0.2% 0.2 0.2% Propylparaben 0.020.02%  0.02 0.02%  Transcutol-P 10  10% 10  10% 20% pluronic gel (20%62.98 62.98%  68.07 68.07%  pluronic F127 and 80% water) Vitamin E 0.20.2% 0.2 0.2% Lecithin 9.9 9.9% 9.9 9.9% Isopropyl myristate 9.9 9.9%9.9 9.9%

Example 5 In Vitro Permeation Through Human Cadaver Skin ofKetamine-amitriptyline Cream and Gel Formulations (Compositions A-J)

[0193] A system employing six improved Franz diffusion cells with adiffusional area of 1.767 cm² (FDC-400, Crown Glass Company, Somerville,N.J.) was used for the permeation studies. The receptor-phase volume was13 ml and the receptor temperature was maintained at 37±0.5° C. with awater jacket. PEG 400/Water (40/60) was used as receptor medium. Humancadaver skin dermatomed at 375 μm (New York Firefighters Skin Bank, NewYork, N.Y.) was hydrated at room temperature in normal saline solutionfor 15 minutes. The skin sample was mounted between the donor andreceptor compartments of the cell and clamped with the dermal side incontact with the receptor medium. About 150 mg of compositions A-J wereapplied to the stratum comeum side. Samples of the receptor fluid (1 ml)were withdrawn at 2, 4, 6, 8, and 24 hours and replaced with the samevolume of receptor medium after each sample was taken. The experimentfor each formulation was conducted in replicates (n=3). The samples wereanalyzed for ketamine and amitriptyline concentrations by HPLC assayprocedure described below. A cumulative amount of ketamine andamitriptyline permeated per unit surface area of the skin was plottedagainst time and the permeation rate (flux=μg/cm²/hr) was determined forketamine and amitriptyline.

[0194] HPLC was performed using a Platinum EPS column© 18, 100 A, 5u,150×4.6 mm, Part No. 32214, Alltech Associates, Inc., Deerfield, Ill.)using commercially available HPLC apparatus. Mobile phase A was 10/90(v/v) Acetonitrile/40 mM potassium phosphate buffer (pH 2.5) with 10 mMheptanesulfonic acid sodium salt as ion paring agent. Mobile phase B was50/50 (v/v) acetonitrile/ 40 mM potassium phosphate buffer (pH 2.5) with10 mM heptanesulfonic acid sodium salt as ion paring agent. The gradientprogram was such that at 0 minutes, a solution of 70% A and 30% B wasused; at 10 minutes, 100% B; at 17 minutes, 100% B; at 18 minutes, 70% Aand 30% B; at 22 minutes, 70% A and 30% B. The flow rate was 1.0 ml perminute; column temperature 40° C.; sample temperature at roomtemperature; injection volume of 25 μl; wavelength 260 nm; back pressurewas approximately 40 kg/cm². For a run time of 22 minutes, under theabove conditions, retention times were as follows: methylparaben, 5.3minutes; ketamine hydrochloride, 7.6 minutes; propylparaben, 10.3minutes; amitriptyline hydrochloride, 14.5 minutes. TABLE 6 KetaminePermeation Data through Human Cadaver Skin Formula permeation rate No.Formula type Strength (μg/cm²/hr) A Composition of the invention High8.64 B Composition of the invention Low 4.09 C Composition of theinvention High 4.77 with Permeation Enhancer D Composition of theinvention Low 4.09 with Permeation Enhancer E Pluronic Gel withPermeation High 1.82 Enhancer F Pluronic Gel with Permeation Low 1.14Enhancer G PLO Gel with Permeation Enhancer High 4.55 H PLO Gel withPermeation Enhancer Low 1.36

[0195] TABLE 7 Amitriptyline Permeation Rate through Human Cadaver SkinFormula permeation rate No. Formula type Strength (μg/cm²/hr) AComposition of the invention High 2.82 B Composition of the inventionLow 2.41 C Composition of the invention High 1.82 with PermeationEnhancer D Composition of the invention Low 1.86 with PermeationEnhancer E Pluronic Gel with Permeation High 0.23 Enhancer F PluronicGel with Permeation Low 0.14 Enhancer G PLO Gel with Permeation EnhancerHigh 0.68 H PLO Gel with Permeation Enhancer Low 0.14

[0196] Compositions A-D, representative compositions of the invention,provide enhanced permeation rates of ketamine and amitriptyline comparedto standard topical formulations E-H. The effect is more pronounced atlow-strength concentrations.

Example 6 Chemical and Physical Stability Studies

[0197] Physical and chemical stability of composition A, arepresentative composition of the invention, was evaluated and comparedaccording to International Conference on Harmonisation (ICH) guidelinesfor Stability Testing of New Drug Substances and Products (Recommendedfor Adoption at Step 4 of the ICH Process on Oct. 27, 1993 by the ICHSteering Committee), hereby expressly incorporated herein by reference.Samples of compositions of the invention were maintained in storagechambers under controlled temperature and relative humidity (“RH”) usinga Stability oven, Model No. ES2000, Environmental Specialties, Inc.,Raleigh, N.C. Three different storage conditions, 25° C./60% RH, 30°C./60% RH, and 40° C./75% RH, were used in the study. At one and twomonths, aliquots were removed, and amitriptyline, ketamine, methylparaben, and propyl paraben were extracted with methanol. The extractswere analyzed by HPLC to determine the percentage of amitriptyline,ketamine, methyl paraben, and propyl paraben remaining in thecompositions and thereby determine whether the compositions had lostactivity through decomposition or otherwise. The extraction and HPLCanalysis was conducted as follows.

[0198] One gram of the compositions of the invention or the gels towhich they were compared was placed in a glass beaker. For low strengthsamples, approximately 30 ml of methanol was added as the extractionsolvent. The sample was stirred in a hot water bath at 70±10° C. forfive (5) minutes, then sonicated in hot tap water (60±10° C.) for five(5) minutes. Ten ml of methanol was added to replace that whichevaporated, and the sample was stirred and sonicated as described above.The beaker was then removed from the water bath and stirred whileallowed to cool to room temperature. Then the sample was transferred toa volumetric flask. The beaker was rinsed with methanol and the rinsingsolvent added to a volumetric flask and methanol was added up to 50 ml.For high-strength samples, the same procedure was used exceptapproximately four times the amount of methanol was used in theextraction. The sample was then filtered through a 0.2 μm PTFE syringefilter. The first 2 ml of filtrate was discarded and the remaining wastransferred to an HPLC vial.

[0199] The amounts of amitriptyline, ketamine, methylparaben, andpropylparaben in the extraction solvent were then determined usinghigh-pressure liquid chromatography. Chemical stability of both theactives and preservatives in emulsion composition A (prepared accordingto Example 1) is presented in Table 8 as the percentage of activesremaining. This value can be compared to the percentage of activescalculated before storage according to the HPLC method. TABLE 8Percentage of Actives Remaining in Composition A After Exposure toStability Testing Conditions calc. percentage of actives calc.percentage of actives calculated initial after storage for one monthafter storage for two months percentage of actives 25° C. 30° C. 40° C.25° C. 30° C. 40° C. Methylparaben 104.4% 103% 102% 102% 101% 102% 102%Propylparaben 101.8% 102% 102% 102% 102% 103% 103% Amitriptyline 102.5%103% 102% 103% 101% 102% 102% Hydrochloride Ketamine 100.4% 103% 102%103% 100% 100% 102% Hydrochloride

[0200] The above stability testing shows that composition A, arepresentative composition of the invention, is chemically stable underthe storage conditions for at least two months even at elevatedtemperatures. Thus, the compositions of the invention show excellentchemical stability.

[0201] After storage of the samples under the above conditions, sampleswere evaluated for physical stability by measuring viscosity andoil-phase droplet size. A Brookhaven™ viscometer (Model RVT, Helipathstand setting, Brookhaven Engineering laboratories, Inc., Middleboro,Mass.) was used to analyze the viscosity of composition A. A T spindlewas used at a 5 rpm rotation speed. The sample temperature wasmaintained at 25° C. during the analysis. The effect of storage on theemulsion viscosity is seen in Table 9.

[0202] The oil-phase droplet diameters (“D” weight mean diameter) wasmeasured via laser-light diffraction (Malvern Mastersizer S LaserDiffractor, Malvern Instruments Ltd., Malvern, UK). Prior to theanalysis, emulsion samples were dispersed in the 6.5% solution ofPEG-100 stearate in purified water. Sample refractive index and carrierfluid refractive index were set at 1.5295 and 1.33 respectively. Defaultsetting for the Presentation and Analysis Model was “OHD” and“Polydisperse”. The effect of storage on the droplet size distributionis seen in Table 9.

[0203] When the same experiment was conducted with pluronic-lecithingels G and H, the samples turned yellow and phase separation occurredduring storage indicating physical and chemical instability. TABLE 9Physical Stability of Composition A following Stability Storage Twomonths Initial 25° C. 30° C. Viscosity (cps) 54,000 66,000 54,000 D10(μm) 0.25 0.25 N/A D50 (μm) 0.34 0.34 N/A D90 (μm) 0.47 0.48 N/A

[0204] The data in Table 9 shows that after two months under the storageconditions, composition A, a representative composition of theinvention, showed minimal change in the viscosity and internal dropletsize. Thus, the compositions of the invention show excellent physicalstability.

Example 7 Other Compositions of the Invention

[0205] Using the procedure of Example 1, a composition of the invention(composition I) having the following composition was prepared. Brij 721, stearyl alcohol, and light mineral oil comprised the oil phase. TABLE10 Compositions I component weight weight % ketamine hydrochloride 2.3 g2.3% amitriptyline hydrochloride 4.5 g 4.5% methyl paraben 0.2 g 0.2%Brij 721 5 g   5% stearyl alcohol 5 g   5% light mineral oil 15 g  15%Brij 72 5 g   5% water 63 g  63%

[0206] The present invention is not to be limited in scope by thespecific embodiments disclosed in the examples, which are intended asillustrations of a few aspects of the invention, and any embodimentsthat are functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

[0207] All cited references are hereby incorporated herein in theirentireties by reference.

What is claimed is:
 1. A emulsion comprising: (a) an antidepressant or apharmaceutically acceptable salt thereof; (b) an NMDA receptorantagonists or a pharmaceutically acceptable salt thereof; (c) alipophilic component; (d) water; and (e) a surfactant, wherein theemulsion is an oil in water emulsion.
 2. The emulsion of claim 1,wherein the mean oil droplet size is within the range of about 0.01microns to about 100 microns.
 3. The emulsion of claim 1, wherein themean oil droplet size is within the range of about 0.1 microns to about10 microns.
 4. The emulsion of claim 1, wherein the antidepressant is anorepinephrine reuptake inhibitor, a selective serotonin reuptakeinhibitor, a monoamine oxidase inhibitor, a serotonin and noradrenalinereuptake inhibitor, a corticotropin releasing factor antagonist, an αadrenoreceptor antagonist, an NK1 receptor antagonist, a 5 HT_(1A)receptor agonist, a 5 HT_(1A) receptor antagonist, a 5 HT_(1A) receptorpartial agonist, an atypical antidepressant, or an other antidepressantor a pharmaceutically acceptable salt thereof.
 5. The emulsion of claim4, wherein the antidepressant is a norepinephrin reuptake inhibitor or apharmaceutically salt thereof.
 6. The emulsion of claim 1, wherein theantidepressant is a tricyclic depressant or a pharmaceuticallyacceptable salt thereof.
 7. The emulsion of claim 6, wherein thetricyclic antidepressant is amitriptyline, desmethylamitriptyline,clomipramine, doxepin, imipramine, imipramine N oxide, trimipramine;adinazolam, amiltriptylinoxide, amoxapine, desipramine, maprotiline,nortriptyline, protriptyline, amineptine, butriptyline, demexiptiline,dibenzepin, dimetacrine, dothiepin, fluacizine, iprindole, lofepramine,melitracen, metapramine, norclolipramine, noxiptilin, opipramol,perlapine, pizotyline, propizepine, quinupramine, reboxetine, ortianeptine or a pharmaceutically acceptable salt thereof.
 8. Theemulsion of claim 1, wherein the antidepressant is amitriptyline or apharmaceutically acceptable salt thereof.
 9. The emulsion of claim 1,wherein an amount of the antidepressant is within the range of about 0.1% by weight to about 10% by weight of a total weight of the emulsion.10. The emulsion of claim 1, wherein the NMDA receptor antagonist is onethat binds to the NMDA receptor at the glycine binding site, theglutamate binding site, the PCP binding site, the polyamine bindingsite, or the zinc binding site or a pharmaceutically acceptable saltthereof.
 11. The emulsion of claim 10, wherein the NMDA receptorantagonist is one that binds to the NMDA receptor at the PCP bindingsite or a pharmaceutically acceptable salt thereof.
 12. The emulsion ofclaim 1, wherein the NMDA receptor antagonist is ketamine,phencyclidine, dextromethorphan, dextrorphan, dexoxadrol, dizocilpine,remacemide, thienylcyclohexylpiperidine, N-allylnormetazocine,cyclazocine, etoxadrol,(1,2,3,4,9,9a-hexahydro-fluoren-4a-yl)-methyl-amine,(1,3,4,9,10,10a-hexahydro-2H-phenanthren-4a-yl)-methyl-amine, PD 138558,tiletamine, kynurenic acid, 7-chloro-kynurenic acid, memantine,6-cyano-7-nitroquinoxaline-2,3-dione, or6,7-dinitro-quinoxaline-2,3-dione or a pharmaceutically acceptable saltthereof.
 13. The emulsion of claim 1, wherein the NMDA receptorantagonist is ketamine or a pharmaceutically acceptable salt thereof.14. The emulsion of claim 1, wherein an amount of the NMDA receptorantagonist is within the range of about 0.1% by weight to about 10% byweight of a total weight of the emulsion.
 15. The emulsion of claim 1,wherein the NMDA receptor antagonist is ketamine or a pharmaceuticallyacceptable salt thereof and the antidepressant is amitriptyline or apharmaceutically acceptable salt thereof.
 16. The emulsion of claim 1,wherein the lipophilic component comprises petrolatum.
 17. The emulsionof claim 1, wherein the lipophilic component comprises a stiffeningagent.
 18. The emulsion of claim 17, wherein the stiffening agent iscetyl alcohol.
 19. The emulsion of claim 1, further comprising alipophilic Intradermal penetration enhancer.
 20. The emulsion of claim19, wherein the lipophilic intradermal penetration enhancer is isopropylmyristate, glycerol monolaurate, glycerol monooleate, glycerolmonolinoleate, isopropyl isostearate, isopropyl linoleate, isopropylmyristate/fatty acid monoglyceride combination, isopropylmyristate/ethanol/L-lactic acid combination, isopropyl palmitate, methylacetate, methyl caprate, or methyl laurate.
 21. The emulsion of claim 1further comprising a humectant or an anti-foaming agent.
 22. A patchcomprising: (a) an antidepressant or a pharmaceutically acceptable saltthereof; (b) an NMDA receptor antagonists or a pharmaceuticallyacceptable salt thereof; (c) a lipophilic component; (d) water; and (e)a surfactant, wherein the emulsion is an oil in water emulsion.
 23. Thepatch of claim 22, wherein the NMDA receptor antagonist is ketamine or apharmaceutically acceptable salt thereof and the antidepressant isamitriptyline or a pharmaceutically acceptable salt thereof.
 24. Amethod of treating pain in a mammal comprising topically administeringto the skin of a mammal in need thereof an emulsion comprising: (a) atherapeutically effective amount of an antidepressant or apharmaceutically acceptable salt thereof; (b) a therapeuticallyeffective amount of an NMDA receptor antagonists or a pharmaceuticallyacceptable salt thereof; (c) a lipophilic component; (d) water; and (e)a surfactant, wherein the emulsion is an oil in water emulsion.
 25. Themethod of claim 24, wherein the emulsion has a mean oil droplet sizewithin the range of about 0.01 microns to about 100 microns.
 26. Themethod of claim 24, wherein the emulsion has a mean oil droplet sizewithin the range of about 0.1 microns to about 10 microns.
 27. Themethod of claim 24, wherein the antidepressant is a norepinephrinereuptake inhibitor, a selective serotonin reuptake inhibitor, amonoamine oxidase inhibitor, a serotonin and noradrenaline reuptakeinhibitor, a corticotropin releasing factor antagonist, an αadrenoreceptor antagonist, an NK1 receptor antagonist, a 5 HT_(1A)receptor agonist, a 5 HT_(1A) receptor antagonist, a 5 HT_(1A) receptorpartial agonist, an atypical antidepressant, or an other antidepressantor a pharmaceutically acceptable salt thereof.
 28. The method of claim27, wherein the antidepressant is a norepinephrin reuptake inhibitor ora pharmaceutically salt thereof.
 29. The method of claim 24, wherein theantidepressant is a tricyclic depressant or a pharmaceuticallyacceptable salt thereof.
 30. The method of claim 29, wherein thetricyclic antidepressant is amitriptyline, desmethylamitriptyline,clomipramine, doxepin, imipramine, imipramine N-oxide, trimipramine;adinazolam, amiltriptylinoxide, amoxapine, desipramine, maprotiline,nortriptyline, protriptyline, amineptine, butriptyline, demexiptiline,dibenzepin, dimetacrine, dothiepin, fluacizine, iprindole, lofepramine,melitracen, metapramine, norclolipramine, noxiptilin, opipramol,perlapine, pizotyline, propizepine, quinupramine, reboxetine, ortianeptine or a pharmaceutically acceptable salt thereof.
 31. The methodof claim 24, wherein the antidepressant is amitriptyline or apharmaceutically acceptable salt thereof.
 32. The method of claim 24,wherein an amount of the antidepressant is within the range of about0.1% by weight to about 10% by weight of a total weight of the emulsion.33. The method of claim 24, wherein the NMDA receptor antagonist is onethat binds to the NMDA receptor at the glycine binding site, theglutamate binding site, the PCP binding site, the polyamine bindingsite, or the zinc binding site or a pharmaceutically acceptable saltthereof.
 34. The method of claim 33, wherein the NMDA receptorantagonist is one that binds to the NMDA receptor at the PCP bindingsite or a pharmaceutically acceptable salt thereof.
 35. The method ofclaim 24, wherein the NMDA receptor antagonist is ketamine,phencyclidine, dextromethorphan, dextrorphan, dexoxadrol, dizocilpine,remacemide, thienylcyclohexylpiperidine, N-allylnormetazocine,cyclazocine, etoxadrol, (1,2,3,4,9,9a-hexahydro-fluoren-4a-yl)-methyl-amine,(1,3,4,9,10,10a-hexahydro-2H-phenanthren-4a-yl)-methyl-amine, PD 138558,tiletamine, kynurenic acid, 7-chloro-kynurenic acid, memantine, 206-cyano-7-nitroquinoxaline-2,3-dione, or6,7-dinitro-quinoxaline-2,3-dione or a pharmaceutically acceptable saltthereof.
 36. The method of claim 24, wherein the NMDA receptorantagonist is ketamine or a pharmaceutically acceptable salt thereof.37. The method of claim 24, wherein an amount of the NMDA receptorantagonist is within the range of about 0.1% by weight to about 10% byweight of a total weight of the emulsion.
 38. The method of claim 24,wherein the NMDA receptor antagonist is ketamine or a pharmaceuticallyacceptable salt thereof and the antidepressant is amitriptyline or apharmaceutically acceptable salt thereof.
 39. The method of claim 24,wherein the emulsion further comprises a lipophilic intradermalpenetration enhancer.
 40. The method of claim 39, wherein the lipophilicIntradermal penetration enhancer is isopropyl myristate, glycerolmonolaurate, glycerol monooleate, glycerol monolinoleate, isopropylisostearate, isopropyl linoleate, isopropyl myristate/fatty acidmonoglyceride combination, isopropyl myristate/ethanol/L-lactic acidcombination, isopropyl palmitate, methyl acetate, methyl caprate, ormethyl laurate.
 41. A method of inducing local anesthesia in a mammalcomprising topically administering to the skin of a mammal in needthereof an emulsion comprising: (a) a therapeutically effective amountof an antidepressant or a pharmaceutically acceptable salt thereof; (b)a therapeutically effective amount of an NMDA receptor antagonists or apharmaceutically acceptable salt thereof; (c) a lipophilic component;(d) water; and (e) a surfactant, wherein the emulsion is an oil in wateremulsion.
 42. The method of claim 41, wherein the emulsion has a meanoil droplet size within the range of about 0.01 microns to about 100microns.
 43. The method of claim 41, wherein the emulsion has a mean oildroplet size within the range of about 0.1 microns to about 10 microns.44. The method of claim 41, wherein the antidepressant is anorepinephrine reuptake inhibitor, a selective serotonin reuptakeinhibitor, a monoamine oxidase inhibitor, a serotonin and noradrenalinereuptake inhibitor, a corticotropin releasing factor antagonist, an αadrenoreceptor antagonist, an NK1 receptor antagonist, a 5 HT_(1A)receptor agonist, a 5 HT_(1A) receptor antagonist, a 5 HT_(1A) receptorpartial agonist, an atypical antidepressant, or an other antidepressantor a pharmaceutically acceptable salt thereof.
 45. The method of claim44, wherein the antidepressant is a norepinephrin reuptake inhibitor ora pharmaceutically salt thereof.
 46. The method of claim 41, wherein theantidepressant is a tricyclic depressant or a pharmaceuticallyacceptable salt thereof.
 47. The method of claim 46, wherein thetricyclic antidepressant is amitriptyline, desmethylamitriptyline,clomipramine, doxepin, imipramine, imipramine N-oxide, trimipramine;adinazolam, amiltriptylinoxide, amoxapine, desipramine, maprotiline,nortriptyline, protriptyline, amineptine, butriptyline, demexiptiline,dibenzepin, dimetacrine, dothiepin, fluacizine, iprindole, lofepramine,melitracen, metapramine, norclolipramine, noxiptilin, opipramol,perlapine, pizotyline, propizepine, quinupramine, reboxetine, ortianeptine or a pharmaceutically acceptable salt thereof.
 48. The methodof claim 41, wherein the antidepressant is amitriptyline or apharmaceutically acceptable salt thereof.
 49. The method of claim 41,wherein an amount of the antidepressant is within the range of about0.1% by weight to about 10% by weight of a total weight of the emulsion.50. The method of claim 41, wherein the NMDA receptor antagonist is onethat binds to the NMDA receptor at the glycine binding site, theglutamate binding site, the PCP binding site, the polyamine bindingsite, or the zinc binding site or a pharmaceutically acceptable saltthereof.
 51. The method of claim 50, wherein the NMDA receptorantagonist is one that binds to the NMDA receptor at the PCP bindingsite or a pharmaceutically acceptable salt thereof.
 52. The method ofclaim 41, wherein the NMDA receptor antagonist is ketamine,phencyclidine, dextromethorphan, dextrorphan, dexoxadrol, dizocilpine,remacemide, thienylcyclohexylpiperidine, N-allylnormetazocine,cyclazocine, etoxadrol, (1,2,3,4,9,9ahexahydro-fluoren-4a-yl)-methyl-amine,(1,3,4,9,10,10a-hexahydro-2H-phenanthren-4a-yl)methyl-amine, PD 138558,tiletamine, kynurenic acid, 7-chloro-kynurenic acid, memantine,6-cyano-7-nitroquinoxaline-2,3-dione, or6,7-dinitro-quinoxaline-2,3-dione or a pharmaceutically acceptable saltthereof.
 53. The method of claim 41, wherein the NMDA receptorantagonist is ketamine or a pharmaceutically acceptable salt thereof.54. The method of claim 41, wherein an amount of the NMDA receptorantagonist is within the range of about 0.1% by weight to about 10% byweight of a total weight of the emulsion.
 55. The method of claim 41,wherein the NMDA receptor antagonist is ketamine or a pharmaceuticallyacceptable salt thereof and the antidepressant is amitriptyline or apharmaceutically acceptable salt thereof.
 56. The method of claim 41,wherein the emulsion further comprises a lipophilic intradermalpenetration enhancer.
 57. The method of claim 56, wherein the lipophilicintradermal penetration enhancer is isopropyl myristate, glycerolmonolaurate, glycerol monooleate, glycerol monolinoleate, isopropylisostearate, isopropyl linoleate, isopropyl myristate/fatty acidmonoglyceride combination, isopropyl myristate/ethanol/L-lactic acidcombination, isopropyl palmitate, methyl acetate, methyl caprate, ormethyl laurate.